Errors in Modern Medicine: The Fear of Estrogen

Rebecca is a 52 year old post menopausal school teacher sitting in my office crying because she knows she needs menopausal hormone replacement if she wants to remain healthy, and yet her primary care doctor and OB/Gyne doctor have both told her estrogen is dangerous, causes breast cancer. Both doctors refused to prescribe hormone replacement for her. In addition, Rebecca’s two closest friends have advised her against it, citing a family member currently diagnosed with breast cancer undergoing chemotherapy. Clearly, Rebecca is torn between two opposing viewpoints, creating mental tension and despair (see left image). This is a recurring scenario all across the country. As is my usual practice, I explained to Rebecca there is no need to make a decision right now, there is plenty of time to study the issue.  I even pointed her to reading material on my blogs, my newsletters, and book discussing the safety and efficacy of menopausal hormone replacement. I then told Rebecca that if she gains a greater understanding and feels more comfortable in the future, I would be glad to get her started on the hormone replacement program. There is no pressure, and I respect whatever decision she feels comfortable with. Finally, Rebecca agreed with the plan and left the office in good spirits. This is a recurring scenario in my office, duplicated in countless doctor’s offices across the country.

Upper left image: Donna Reed 1941 movie trailer courtesy of Wikimedia Commons

Errors in Modern Medicine

One of the most glaring errors in conventional medicine is the false idea that Estrogen is somehow bad, and causes breast cancer, blood clots, other adverse effects. Modern medicine falsely says that estrogen should never be prescribed for the post-menopausal female, and especially never to breast cancer survivors. The resulting mass media propaganda campaign creates fear of estrogen throughout the population. Nothing could be farther from the truth. The reality is Menopausal Hormone Replacement with estrogen is safe and effective. Not only does estrogen not cause breast cancer, it is actually preventive of breast cancer. I will show you the studies why this is true. When applied via the transdermal route with topical creams, estrogen is safe and does not cause blood clotting. That is why we use transdermal creams and avoid oral estrogen tablets (which are associated with blood clots, increased coagulation, deep venous thrombosis and pulmonary embolus). For more on this topic see The Safety of Transdermal vs Oral Estrogen.

Premarin-Alone (Estrogen) Users Have 23 percent less Breast Cancer Than Placebo

The second arm of the WHI study included 10,739 post-menopausal women after hysterectomy randomized to estrogen (Premarin, CEE) or to placebo. In 2004, the data from the second arm of the Women’s Health Initiative (WHI) was published  in JAMA 2004. This data included 6.8 years of follow up showing 23% less invasive breast cancer in the Premarin treated group (also called CEE) compared to placebo group. There were  94 breast cancer cases in the estrogen hormone group (CEE) and 124 cases of breast cancer in the placebo group. (52-53)

Above Table Results from WHI Second Arm Estrogen Alone 2004:
Green Ellipse shows Hazard Ratio for Breast Cancer of 0.77 (23% less breast cancer in estrogen alone group), Red Ellipse Hazard ratio for E2+MPA in HERS Trial , and E2+MPA in WHI Trial (first arm) showing 30% and 26% increased breast cancer. Table courtesy of Hulley, Stephen B., and Deborah Grady. “The WHI estrogen-alone trial—do things look any better?.” Jama 291.14 (2004): 1769-1771.  (c) Amercan Medical Association.(53)

Estrogen Group Second Arm of WHI: 45% Reduction in Mortality from Breast Cancer

The 18 year follow up showed a 45 percent reduction in mortality from breast cancer in the estrogen treated group compared to placebo. In 2018, Dr.Howard Hodis reviewed the 18 year follow up of the Second Arm of the WHI (Premarin-Alone) showing a 45 percent reduction in breast cancer mortality in the estrogen user group !! Dr. Howard Hodis writes:

After 18 years of cumulative follow-up of the WHI-CEE cohort, breast cancer mortality was statistically significantly reduced by 45% (HR, 0.55; 95% CI, 0.33–0.92). This may well be the most significant and most over-looked finding of the WHI-CEE trial (2).

Above WHI Data Chart Fig 2: Breast Cancer Mortality for First and Second Arms of WHI 18 year follow up. Green Ellipse HR=.55 (45% reduction in breast cancer mortality for Estrogen Alone). Red Ellipse HR= 1.44 (44% increase in breast cancer in E2+MPA) Courtesy of 1) Manson, JoAnn E., et al. “Menopausal hormone therapy and long-term all-cause and cause-specific mortality: the Women’s Health Initiative randomized trials.” JAMA 318.10 (2017): 927-938. (1)

Breast Cancer Mortality in Both Arms of WHI – 18 Year Follow Up

Here is the Above Fig 2 Data on the cumulative breast cancer mortality for the 18-year follow-up of 2 randomized clinical trials WHI First and Second Arms, between 1993 and 1998 and followed up through December 31, 2014. (See above Data Chart)

First Arm Breast Cancer Mortality E2+MPA  61 vs Placebo=40
Hazard Ratio (HR)=1.44 meaning a 44% increase in breast cancer mortality.

Second Arm Breast Cancer E2 =22 vs Placebo= 41
Hazard Ratio (HR)= 0.55 = 45% reduction in breast cancer mortality

Premarin Plus Medroxyprogesterone – First Arm of the Women’s Health Initiative 26 percent greater Breast cancer in Hormone Users

Remember there are two arms of the WHI. We discussed the second arm from 2004 above. Now, we will go back two years to 2002 and discuss the first Arm.

In 2002, the first Arm of the Women’s Health Initiative (WHI) was published in JAMA, halted early after 5.2 years because of increased breast cancer in the estrogen treated group. This study created havoc in medical practice and in the general population. Fear of estrogen made women stop requesting and doctors stop prescribing Hormone Replacement Therapy (HRT). Following this 2002 publication in JAMA, the entire previous medical edifice of menopausal hormone replacement was dismantled. Training programs disappeared. New doctors no longer had training or expertise to even practice hormone replacement. (54)

The first arm of the WHI randomized 16,608 post-menopausal women to either Prempro (Premarin plus Medroxyprogesterone) or placebo. After 5.2 years of follow up, there were 290 cases of breast cancer in the Prempro group which is 26% greater than the placebo group.  The authors write:

Estimated hazard ratios (HRs) (nominal 95% confidence intervals [CIs]) were as follows: CHD, 1.29 (1.02-1.63) with 286 cases; breast cancer, 1.26 (1.00-1.59) with 290 cases; stroke, 1.41 (1.07-1.85) with 212 cases; PE, 2.13 (1.39-3.25) with 101 cases; colorectal cancer, 0.63 (0.43-0.92) with 112 cases; endometrial cancer, 0.83 (0.47-1.47) with 47 cases; hip fracture, 0.66 (0.45-0.98) with 106 cases; and death due to other causes, 0.92 (0.74-1.14) with 331 cases.(54)

Synthetic Progestins Are Carcinogenic

The synthetic progestin, medroxyprogesterone (MPA), is a known breast cancer carcinogen, and commonly used to induce breast cancer in animal models.  On the other hand, attempted induction of breast cancer in the animal lab using natural progesterone has always failed. (55-59)

In 2020, Dr. Kathryn B. Horwitz reviewed the past 90 years of progesterone receptor research and the role of the progesterone receptor (PR) in ‘tumorigenesis’. Firstly Dr Horwitz debunks the idea that natural progesterone is carcinogenic, stating progesterone is incapable of causing breast cancer. On the other hand synthetic progestins, such as MPA [medroxyprogesterone], norethindrone acetate, and levonorgestrol are confirmed breast carcinogens with 200% increased incidence of breast cancer in long term users, writing:

In the early 2000s, the somewhat surprising finding that prolonged use of synthetic progestin-containing menopausal hormone therapies was associated with increased breast cancer incidence raised new questions about the role of PR in ‘tumorigenesis’…First, we need to debunk the notion that progesterone ‘causes’ breast cancers. There is considerable experimental and clinical evidence that, alone and at physiological levels, progesterone is incapable of causing breast cancers so that its reputation as a ‘tumorigenic’ or ‘carcinogenic’ hormone is undeserved. It would be useful to have definitive proof of this once and for all and to eliminate use of these terms in reference to progesterone and the breast…A 2019 meta-analysis by the Collaborative Group on Hormonal Factors in Breast Cancer confirmed the increased risk of breast cancer for MHT [Menopausal Hormone Therapy] containing MPA [medroxyprogesterone], norethindrone acetate, or levonorgestrol, compared to never users or estrogen-only users (Collaborative Group on Hormonal Factors in Breast 2019). This was especially pronounced for long-term (>10 year) progestin users, who had twice the risk of developing breast cancer. Notably, this meta-analysis did not include bioidentical progesterone formulations, which had either no additional risk or even decreased breast cancer risk (discussed in Piette 2018)…Furthermore, it is important to distinguish between progestins and natural progesterone. Currently these tend to be lumped together leading to the view that progesterone is ‘carcinogenic’ (i.e. cancer causer). It is our opinion that natural progesterone does not ‘cause’ breast cancer but can expand it (see subsequent section). Hence, despite widespread linkage between the terms ‘progestins’ and ‘carcinogenesis’, we suggest that care must be taken with these ideas, as with the term ‘bioidentical’, until solid data are available, in women, differentiating between the natural hormone and any biosynthetic ones.(59)

The WHI Trial Did Not Study Women’s Hormones At All !!

In 2011, Dr. Cynthia L. Bethea, an expert in doing hormone research in primates at the Oregon National Primate Research Center, reviewed the catastrophic findings of the first arm of the WHI study showing increased breast cancer risk from menopausal hormone replacement. Dr. Bethea remarks these WHI findings were considered an indictment of menopausal hormone replacement, when in fact, the WHI trial did not study women’s hormones at all, which would have required the use of natural hormones, estradiol and progesterone, Remember this WHI first arm study used Premarin and Provera (MPA, medroxyprogesterone). Premarin is estrogen derived from a pregnant horse, and MPA is a synthetic progestin which does not occur naturally in the human body or anywhere else in nature. To study women’s hormones would have required the use of human bioidentical  hormones in a combination of human estrogen (usually estradiol and estriol), natural progesterone, and natural testosterone, all present naturally in the human body. Dr. Cynthia L. Bethea writes:

While the WHI trial [first arm] made a valuable contribution in revealing the risks associated with conjugated equine estrogens [Premarin, CEE] plus MPA [medroxyprogesterone] treatment in postmenopausal women, it unfortunately generated considerable controversy in the field because it was interpreted as an indictment of postmenopausal hormone replacement, when in fact, it did not study hormone replacement at all: that would have required use of the natural hormones, estradiol and progesterone. The actions of the natural hormones are significantly different from those of Premarin and MPA. (60)

Re-Analysis of First Arm WHI Data Shows Glaring Error

In 2018, Dr. Howard Hodis and Phillip Sarrel re-analyzed the data from the WHI first and second arms. They found an error in the study. Some of the women in the placebo group had a history of prior HRT (Hormone Replacement Therapy) use. These women should have been removed from the placebo group, and were not. The prior use of estrogen confers protection from breast cancer, and falsely reduces the incidence of breast cancer in the placebo group. If the women with prior HRT use are removed from the placebo group, the data chart (see Figure 1 below) looks entirely different. There is a null effect, meaning no difference between the Prempro group and the Placebo group in terms of breast cancer incidence.  Dr. Howard Hodis writes:

In fact, the increased HR [Hazard Ratio] was not due to an increased breast cancer incidence rate in women randomized to CEE + MPA [Prempro] therapy but rather due to a decreased and unexpectedly low breast cancer rate in the subgroup of women with prior HT [Hormone Therapy] use randomized to placebo. For women who were HT naïve when randomized to the WHI, the breast cancer incidence rate was not affected by CEE + MPA therapy relative to placebo for up to 11 years of follow-up…the data clearly show that CEE+MPA therapy had a null effect on breast cancer risk particularly in the subgroup of women representing the typical population of women treated with HT who are HT naïve before receiving menopausal HT…it is clear that breast outcome data from the WHI-CEE+MPA trial has been misinterpreted and overgeneralized. (2)

SEE Below FIG. 1: There are two different placebo groups. Left Chart shows placebo group with no prior hormone use. Notice Invasive breast cancer trend lines are superimposed.  Right Chart shows placebo group with prior hormone use: Notice divergence in trend lines for breast cancer (Red Arrows). This divergence accounts for the false impression of increased cancer risk in the Prempro (Premarin +MPA) Group. This shows that prior hormone use is breast cancer protective! (2)

Above image Fig. 1 Courtesy of Hodis, Howard 2018: It is the divergence (Red Arrow- Right Chart)  in the trend line for women with prior hormone therapy use randomized to placebo that accounts for the elevated hazard ratio for breast cancer falsely giving the impression that breast cancer incidence was increased in the trial due to conjugated equine estrogen plus medroxyprogesterone acetate where in fact the elevated hazard ratio was due to a DECREASED breast cancer incidence In the PLACEBO treated group. (2)

Dr. Rowan Chlebowski, December 2019-Estrogen Alone 44% reduction in Mortality from Breast Cancer

In 2019, Rowan Chlebowski MD, PhD, chief of the Division of Medical Oncology and Hematology at Harbor-UCLA Medical Center reviewed the 16.1 year follow up data from the WHI study showing Premarin-Only users (estrogen only first arm 2004 JAMA) were 23% less likely to be diagnosed with breast cancer, and 44% less likely to die from breast cancer, writing:

After 16.1 years of cumulative follow-up…Compared with women who had received placebo, those who had received CEE [Premarin] were 23 percent less likely to have been diagnosed with breast cancer and 44 percent less like to die from the disease…After 18.3 years of cumulative follow-up, among those who received CEE plus MPA, …Compared with women who had received placebo, those who had received CEE plus MPA were 29 percent more likely to have been diagnosed with breast cancer…Estrogen alone decreased, while adding progestin increased, breast cancer incidence…CEE-alone [Premarin-Alone] and CEE plus MPA [Medroxyprogesterone] use have opposite effects on breast cancer incidence. CEE alone significantly decreases breast cancer incidence which is long term and persists over a decade after discontinuing use. CEE plus MPA use significantly increases breast cancer incidence which is long term and persists over a decade after discontinuing use. (3)

Dr. Lindsay Berkson: Nothing Else Like Estrogen Therapies Has Ever Been Shown to Be So Breast Protective.

On October 2023, Dr Lindsay Berkson discussed this issue on her substack blog, writing:

The WHI 1 authors forgot to ask, and thus did not remove, in the placebo group, any women who had already taken estrogen therapies…Since estrogen was ultimately, on re-analysis found to be “breast protective” , and the synthetic progestins were huge adverse contributing issues, this made the incidence of breast cancer in the placebo group of ladies, lower, as women had already taken the protective estrogen…This made the experimental arm, women taking hormones, falsely appear as though they had more cases of breast cancer…When the data was re-analyzed, thus “righted” by taking out this “confounding issue”, and longer term effects of estrogen looked at with a fine tooth comb, the same original authors, re-published their re-analysis. This is now what I call the WHI 2…Conclusions of WHI 2: Women taking estrogen replacement therapy (ERT) had 23% less incidence or chance of getting breast cancer in the first place. And if you had been on ERT, and got breast cancer, you had a 44% decreased chance of dying from it. Progestins were more the breast damaging issue. Not estrogen. So, stunning as it is, being on ERT put you in a better position, even if you went on to get breast cancer! This is something that is now replicated. Substantiated. But not taught in most med schools or appreciated by most docs and women. Or lawyers!…Estrogen “protects” healthy breast tissue from getting breast cancer in the first place. And, if a women has been on estrogen therapies for an average of 5 years and then gets breast cancer, the estrogen therapies “reduce” her risk of dying from breast cancer by 44%. Nothing else like estrogen therapies has ever been shown to be so breast protective. (4)(45-48)

Natural Progesterone is also Breast Cancer Preventive

In 2017, Dr. Allan Lieberman reviewed the medical literature on progesterone as a breast cancer preventive agent, finding that a common error is confusing natural progesterone with the synthetic progestins such as MPA, thus falsely attributing to progesterone the carcinogenic properties of progestins. Dr. Allan Lieberman writes:

The literature is extensive on the effects of estrogen and progesterone and their relationships to breast and other cancers and other health-related effects. Much of the medical literature on progesterone or progesterone-like compounds is contradictory,1-5 with progesterone sometimes implicated as a cause of breast cancer. These contradictory results are the result of researchers confusing the effects of synthetic progestins with those of natural progesterone…To avoid confusion surrounding the long-term health benefits and consequences of using  progestogenic drugs, we recommend that the term progesterone be used only for the naturally occurring progestogen, P4, whereas the term progestin be used for any of the synthetic versions. The interchangeable use of these terms in scientific, medical, and lay articles confounds the interpretation of data from these different classes of progesterone receptor (PR) ligands and their implications for human health…The evidence strongly suggests that natural progesterone is protective and preventive of breast cancer…The authors wish to emphasize that natural progesterone is preventive of breast and endometrial cancer, and physicians should have no hesitation prescribing it. (65)

Two French Studies Using Estradiol and Micronized Progesterone

In 2007, Dr. Stephen Birrell reviewed the medical literature on synthetic progestins increasing risk for breast cancer via disruption of androgen receptor signalling. Dr. Birrell comments that when natural progesterone (micronized) is used instead of synthetic progestins, no such carcinogenic effects are observed. Dr. Birrell cites two French studies using micronized progesterone and estradiol for menopausal hormone replacement in which there was no observed increase in breast cancer, the E3N-EPIC cohort of 54,548 women by Dr. Fournier (2005) and a smaller study by Dr. de Lignieres (2002) of 3,175 women, writing:

Notably, in France the majority of women taking combined HRT [Hormone replacement Therapy] receive oral micronized progesterone rather than a synthetic progestin. In two French studies- the E3N-EPIC cohort of 54,548 women and a smaller study of 3175 women, no significant increase in breast cancer risk due to HRT use with micronized progesterone was observed compared with untreated women. (49-51)

The Use of Estradiol Alone – 30 percent Increased Risk for Breast Cancer

Notice the above WHI second arm study showed reduced incidence of breast cancer with use of estrogen. However this estrogen was not human 17-Beta-estradiol. They used pregnant horses estrogen called CEE (conjugated equine estrogen). In addition the women were started after a long period of estrogen deprivation (LTED). What about the use of estradiol-alone in women started shortly after menopause without LTED, without long term estrogen deprivation? This was discussed in a previous newsletter: The Safety of Bioidentical Hormones, in which we presented three large observational studies, the 2008 French E3N Cohort study by Dr. Agnes Fournier, the 2006 Finland study by Dr. Heli Lyytinen, and the  2011 EPIC study by Dr. Kjersti Bakke.  All three observational studies were in close agreement that estradiol alone without LTED increases breast cancer risk by about 25-30 percent. Increased breast proliferation with estradiol was also found by Dr. Wood using primates to study the two different variants of estrogen, estradiol and CEE (premarin) which is discussed below.

Premarin (CEE) is Less Proliferative than Estradiol

In 2008, Dr. Charles E. Wood studied hormones administered to primates in his lab in Winston Salem.  Dr. Wood used the KI-67 marker in a primate model to compare proliferative effects of CEE (Premarin, horse estrogen) to that of 17-Beta Estradiol  (human estrogen) when used as hormone replacement in a primate model, finding highly significant 259-330% increase in breast cell proliferation in estradiol treated monkeys compared to controls. However, in the Premarin (CEE) treated monkeys there was far less breast cell proliferation, only 75% was noted compared to controls using the KI-67 antigen test of cell proliferation. As Dr. Barbara Levy mentions in 2024, CEE contains B ring steroids which preferentially bind to and activate ER-Beta, thus explaining CEE less proliferative effects when compared to 17-Beta-estradiol. Other hormones with ER-Beta binding preference are estriol (E3) and testosterone metabolite 3Beta-diol, thus explaining their cancer protective properties. These are discussed elsewhere.(108-111)

CEE and B-ring Steroids are Breast Cancer Preventive

In 2015, Dr. Valerie Flores discusses the mechanism of action to explain the less proliferative effect of CEE (horse estrogen) compared to estradiol (human estrogen). Horse estrogen (CEE) contains a mixture of eleven estrogens, many of which are B-ring steroids which bind preferntially to ER-Beta, thus downregulating the proliferative ER-alpha receptor, and explaining the less prolifertive effect of CEE compared to estradiol, writing:

The choice of CEE [horse estrogen] in the ET arm [estrogen only second arm] of the WHI may explain the favorable effects seen on the breast. CEE contains a mixture of multiple estrogens, and each estrogen-type not only preferentially binds the two estrogen receptors, but may also exert differential actions depending on the target tissue. While E2 [human estradiol] is the well characterized estrogen, less is known about the many estrogenic components of CEE. Unlike E2, these other estrogens differ in their B-ring saturation and in their chemical moieties at the 17-position…Bhavnani et al analyzed the effects of 11 equine estrogens (in CEE preparations) on the transcriptional activity of ER alpha and beta, and found that many of the equine estrogens preferentially bind ER beta. ER beta activation can inhibit ER alpha activity on cell proliferation. This inhibition induced by equine estrogens may in part explain the decreased risk of breast cancer observed in the WHI ET study.…Additional research identifying which equine estrogens exert more SERM-like [Seletive Estrogen Receptor Modulator] properties is needed, as they can not only be preferentially used in menopausal hormone therapy (MHT), but perhaps may even be of benefit in the treatment of breast cancer. (113)

With the above knowledge of the CEE (horse estrogen) have less proliferation effects than estradiol, one might ask the next logical question, why not use CEE (horse estrogen) for all menopausal hormone replacement? After all, CEE (horse estrogen) was studied in the WHI (Women’s health Initiative ) randomized controlled trial and was found to reduce breast cancer risk by 23 per cent compared to placebo. This proves CEE is breast cancer preventive. My answer is that using CEE as the estrogenic component for menopausal HRT certainly is a good choice. The B-Ring steroid component of CEE targets preferentially the ER-Beta, thus downregulating proliferative effects, and serves as a breast cancer preventive.  However, a better approach is to use human estradiol combined with estriol as the estrogen component. The estriol preferntially targets ER-Beta. In addition, we always add progesterone which is a brake on ER-Alpha proliferative effects, as demonstrated in 2015 by Dr. Hisham Mohammed. In addition, we add Testosterone which is metabolized to 3-Beta Diol which preferentially binds to and activates ER-Beta. So, as you can see, we have created a hormone symphony, i.e. a combination of estriol, progesterone and testosterone all serving to downregulates the proliferative effects of estradiol. We know from the French Cohort study by Dr. Agnes Fournier that addition of natural progesterone to estradiol reduces the HR 1.25 for breast cancer back down  to 1.00. In other words, the overall risk of breast cancer is the same as the general population. By further adding testosterone, we now have an excellent breast cancer prevention program which reduces breast cancer risk by 40 percent according to Dr Rebecca Glaser’s studies. The net result is an excellent menopausal HRT program providing a good breast cancer prevention program. (115-125)

For more on Testosterone as a Breast Cancer Preventive see: Testosterone for Prevention and Treatment of Breast Cancer.

In 2020, Dr. Rahul Mal reviewed the medical literature on ER-Beta as a broad spectrum ligand activated tumor suppressor which could potentially be a treatment strategy for breast and multiple other cancers, writing:

High ERβ1 expression is associated with improved overall survival in women with breast cancer. The promise of ERβ activation, as a potential targeted therapy, is based on concurrent activation of multiple tumor suppressor pathways with few side effects compared to chemotherapy. Thus, ERβ is a nuclear receptor with broad-spectrum tumor suppressor activity, which could serve as a potential treatment target in a variety of human cancers including breast cancer. Further development of highly selective agonists that lack ERα agonist activity, will be necessary to fully harness the potential of ERβ… As with ERα, estrogenic compounds including estradiol, estrone, and estriol activate ERβ. Relative to ERα, ERβ binds estriol and ring B unsaturated estrogens with higher affinity, while the reverse is true of 17β-estradiol and estrone (7–10). On the other hand, the dihydrotestosterone metabolites 5-androstenediol and 3β androstanediol are relatively selective (3-fold) for ERβ over ERα (11). (116)

Our Breast Cancer Prevention Program

1) Our office uses human bioidentical progesterone, avoiding the carcinogenic synthetic progestins such as medroxyprogesterone (MPA) and norethindrone (see below chart). In 2014, the mechanism of carcinogenicity of MPA was illucidated by Dr. Aleksandra M. Ochnik, finding it is the anti-androgenic effect of MPA causing the problem, writing:

DHT [Di-Hydro-Testosterone] inhibited the proliferation of breast epithelial cells in an AR [Androgen Reeptor]-dependent manner within tissues from postmenopausal women, and MPA significantly antagonized this androgenic effect. ..MPA significantly opposed the positive effect of DHT on AR  [Androgen Receptor] stabilization, but these hormones had no significant effect on estrogen receptor α or progesterone receptor levels….In a subset of postmenopausal women, MPA [medroxyprogesterone] exerts an antiandrogenic effect on breast epithelial cells that is associated with increased proliferation and destabilization of AR protein [Androgen Receptor]. This activity may contribute mechanistically to the increased risk of breast cancer in women taking MPA-containing EPT [estrogen/progestin therapy]. (114)

2) Our office uses Bi-Est which is 80% Estriol (E3) and 20% Estradiol (E2). Estriol is breast cancer protective. Both Estriol (E3) and metabolites of Testosterone predominantly target the ER Beta Receptor (Estrogen Receptor Beta) which is tumor suppressor. (61)

3) My office uses oral micronized progesterone, FDA approved (Solvay December 1998) for prevention of endometrial hyperplasia. Usual dosage is micronized progesterone 100 mg oral capsule taken at bedtime. (62-65)

4) My office tests for iodine levels and supplements iodine when low: Iodine decreases breast cancer risk and is useful in treatment of breast cancer. (See: Iodine Treats Breast Cancer) (74)(112)

5) My office uses Testosterone for all women- Testosterone is an androgen and is breast cancer preventive, decreasing breast cancer risk by 39-40 per cent. The mechanism of action is preferential activation of ER-Beta by a metabolite of testosterone 3-Beta-Diol. (See: Testosterone for Prevention and Treatment of Breast Cancer) (75)

6) My office uses DIM (Di-Indole-Methane) for all women. DIM diverts estrogen metabolism toward favorable metabolic pathways. (23)(66-69) (94-99)

Dr. Ercole Cavalieri Breast Cancer Caused by Catechol Estrogen 3,4, Quinones

Although estrogen itself is protective of breast cancer, some estrogen metabolites are carcinogenic. Normally, these quinone-estrogen metabolites are disposed of by normal metabolic pathways. However some women have genetic abnormalities leading to bottlenecks in estrogen metabolism pathways which accumulate carcinogenic estrogen metabolites (4-hydroxy-quinones). In 2021, Dr. Ercole Cavalieri studied breast cancer formation caused by reactive metabolites of estrogen called catechol estrogen 3,4, quinones. These metabolites of estrogen are oxidative and will attach to estrogen receptors on DNA causing oxidative damage to the DNA. Oxidative damage leads to DNA mutations and cancer. Dr. Ercole Cavalieri writes:

Cancer can be initiated by increased formation of reactive estrogen metabolites called catechol estrogen-3,4-quinones. If estrogen metabolism becomes unbalanced and significant amounts of these quinones arise, depurinating estrogen-DNA adducts are primarily formed, leading to cancer-causing mutations.(94)

How do we avoid these harmful DNA adducts, the 4-hydroxy estrogen quinones? This is discussed below:

7) My office gives all women methyl-folate in a good multivitamin: Methylation defects (MTHFR polymorphisms) increase breast cancer risk. This is treated with methyl-folate, provided in most high quality multivitamins. Reveratrol, NAC (N-Acetyl cysteine) and sulforaphane have been found beneficial in patients with genetic mutations (SNPs) which impair estrogen metabolism and leading to accumulation of carcinogenic quinone-estrogen adducts. (76) (94-99)

8) My office tests for selenium levels and supplements when found low:  selenium deficiency is a risk factor for all cancers. Selenium is a cancer preventive agent. (71-73)(112)

9) What About Screening Mammography?

My office does not recommend screening mammography on the healthy population because screening mammography results in overdiagnosis and overtreatment harms. In 2009, in JAMA, Dr. Laura Esserman, professor of surgery and radiology at UCSF and director of the UCSF Breast Care Center since 1996, reviewd 20 years of national breast cancer mortality data finding the national program of screening mammography has not resulting in the anticipated reduction in cancer mortality. In 2021, Dr. Amanda E Kowalski  showed any mortality reduction associated with screening mammography is outweighed by increased mortality from over-treatment. In 2023 in JAMA, Dr. Michael Bretthauer conducted a meta-analysis of all screening tests showing screening mammography does not save lives by extending lifetime, writing:

The findings of this meta-analysis suggest that current evidence does not substantiate the claim that common cancer screening tests save lives by extending lifetime, except possibly for colorectal cancer screening with sigmoidoscopy. (79)

The second reason we do not do routine screening mammography is that breast tissue is superficial and accessible to self-examination, leading the patient to present the “lump in the breast” to her physician who will then order a diagnostic mammogram and ultrasound for evaluation. The third reason is that heavy mass media marketing for screening mammography convinces women this is a form of breast cancer prevention. This is gives a false sense of security. Screening mammography does not prevent anything. Rather it gives a radiographic image of the breast, a snapshot in time. While indolent breast cancers such as DCIS (ductal carcinoma in situ) will be detected by the tell-tale punctate cacifications, aggressive breast cancers will arise in between screening mammograms and come to the patients attention through self examination because they are superficial and cause symptoms. A more logical and effective Breast Cancer Prevention Program is listed above using ER-Beta Ligands estriol, testosterone, progesterone.  Other breast cancer preventives include iodine, selenium, vitamin D3, DIM, methy-folate sulforaphane, reveratrol, etc. For more on screening mammography, see: Laura Esserman Questions Screening Mammography. (29-33)(79)

See below listing of progesterone and synthetic progestins. Progesterone is protective, all other synthetic progestins are carcinogenic:

Nexplanon (Pro) Generic name: etonogestrel
Mirena (Pro)Generic name: levonorgestrel
Depo Provera (Pro) Generic name: medroxyprogesterone
Implanon (Pro) Generic name: etonogestrel
Kyleena (Pro) Generic name: levonorgestrel
Skyla (Pro) Generic name: levonorgestrel
Liletta (Pro) Generic name: levonorgestrel
Slynd (Pro) Generic name: drospirenone
Provera (Pro) Generic name: medroxyprogesterone
Errin (Pro) Generic name: norethindrone
Nora-Be (Pro) Generic name: norethindrone
Makena (Pro) Generic name: hydroxyprogesterone
Ortho Micronor (Pro) Generic name: norethindrone
Camila (Pro)Generic name: norethindrone
Jolivette (Pro) Generic name: norethindrone
Lyza (Pro) Generic name: norethindrone
Heather (Pro) Generic name: norethindrone
Jencycla (Pro) Generic name: norethindrone
Sharobel (Pro) Generic name: norethindrone
Norlyda (Pro) Generic name: norethindrone
Prometrium (Pro) Generic name: progesterone
depo-subQ provera 104 (Pro) Generic name: medroxyprogesterone
Aygestin (Pro) Generic name: norethindrone
Megace (Pro)Generic name: megestrol
Deblitane (Pro) Generic name: norethindrone
Tulana Generic name: norethindrone
Megace ES (Pro) Generic name: megestrol
Incassia (Pro) Generic name: norethindrone
Nor-QD Generic name: norethindrone
Crinone Generic name: progesterone
Norlyroc Generic name: norethindrone
Lyleq (Pro) Generic name: norethindrone
Prochieve Generic name: progesterone
Ovrette Generic name: norgestrel
Opill (Pro) Generic name: norgestrel
Her Style Generic name: levonorgestrel
Endometrin (Pro) Generic name: progesterone
Emzahh Generic name: norethindrone
Affodel Generic name: norethindrone

Above List of Progestins courtesy of Drugs.com. Notice progesterone has been mistakenly included as a progestin, accounting for the frequent errors in many medical studies which conclude that progesterone is carcinogenic. Pharmaceutical Progesterone is chemically identical to the progesterone made by the ovary. Progestins are synthetic compounds, chemically altered versions of progesterone which are carcinogenic to breast tissue. Progesterone is breast cancer protective, while synthetic progestins are carcinogenic.

Above chart courtesy of Siddique, Y. H., and M. Afzal. “A review on the genotoxic effects of some synthetic progestins.” Int J Pharmacol 4.6 (2008): 410-30. Again, note that natural progesterone has mistakenly been included in the chart for progestins. Natural progestreone is not genotoxic, while all other progestins are genotoxic. (5)

Exposure to Exogenous estrogen (ERT) Prevents Breast Cancer.

In 2022, Dr. Isaac Manyonda reviewed the 20 year follow up of the WHI (estrogen only, second arm 2004 JAMA) showing exposure to exogenous estrogen prevents breast cancer and is protective against osteoporosis and cardiovascular disease, writing:

The WHI [Womens Health Initiative] study of ERT [CEE estrogen replacement, second arm] versus placebo in women with a prior hysterectomy is a most robust piece of research: prospective, randomized, placebo-controlled and with a 20-year follow-up, which now compels a direct interpretation of its finding, namely that exposure to exogenous estrogen (ERT) prevents breast cancer. This is of profound importance, not only in relation to the prevention of the most common cancer in women in the western world, but also because estrogen, whilst being cost-effective and well-tolerated also has other preventative properties against osteoporosis and cardiovascular disease, to name but two. (77)

Estrogen Induces Apoptosis of Breast Cancer Cells

In 2011, Dr Andrea Vasconsuelo, Andrea discussed the role of 17β-estradiol for induction of apoptosis of breast cancer cells, finding this will occur after long term estrogen deprivation or after long term treatment with anti-estrogen drugs (Tamoxifen or aromatase inhibitors)  causing upregulation of Er-Beta receptors on the breast cancer cells,  writing:

However, under some specific conditions E2 [estradiol] could trigger apoptosis in breast cancer cells, opposed to its well studied antiapoptotic role. This peculiar hormone behavior has been observed in cells from breast cancer which have been longterm estrogen-deprived (LTED) or treated exhaustively with antiestrogens. Curiously, the paradoxical induction of apoptosis by estrogen has been established under several unusual circumstances. For example, in this case, the pre-conditions of prolonged estrogen depletion or exhaustive treatment with anti-estrogens of the breast cancer cells are mandatory requisites to trigger apoptosis by E2 and could explain the dual action of the steroid to stimulate growth or apoptosis. Thus, the development of antihormone resistance over years of therapy, reprograms the survival mechanism of the breast cancer cell so that estrogen no longer functions as a survival factor but as a death signal. (12)

Dr. V. Craig Jordan and the Estrogen Deprivation Gap

In 2020, Dr. V. Craig Jordan, perhaps the world’s most greatest and most prolific expert in breast cancer research, and pioneer in use of Tamoxifen, currently Professor of Breast Medical Oncology and Molecular and Cellular Oncology, at MD Anderson Cancer Center, in Houston, reviewed the molecular mechanism for the decreased cancer incidence in the estrogen alone arm of the Women’s Health Initiative, pointing out that after a 5 year gap of estrogen deprivation in post-menopasal women, high dose estrogen is a successful treatment for breast cancer, writing:

A sustained beneficial antibreast cancer action of estrogen alone noted in the WHI study is counter intuitive because the dogma is that estrogen, through the estrogen receptor (ER), is the primary signal for the initiation and growth of breast cancer…However, the paradox (2), which is maintained throughout the WHI evaluation of more than 12 years, is estrogen causes a decrease in mortality and a decrease in the incidence of new breast cancers. This is counter intuitive to the scientific and medical community unless one embraces and understands the known clinical evidence that governs safe estrogen use for the treatment of breast cancer after menopause (3, 4). These were established 70 years ago….An estrogen deprivation gap of 5 years after menopause is required for high-dose estrogen to be an effective treatment for breast cancer…In addition, the same applies to 5 years of adjuvant tamoxifen therapy when recurrence and mortality continue to decrease after adjuvant tamoxifen treatment is stopped. (84)

In 2022, Dr. V Craig Jordan provides a mechanistic insight into the use of estrogen for prevention and treatment of breast cancer, commenting that giving estrogen to menopausal women after long term estrogen deprivation produces a sustained decrease in breast cancer, while the addition of MPA not only reverses this estrogen protective effect, but also increase carcinogenesis, writing:

The clinical description and discovery of estrogen-induced apoptosis [programmed cell death] with further clinical application in two Karnofsky lectures, separated by 38 years, has now provided a mechanistic insight into the adjuvant treatment of breast cancer (62), an insight into the “unexpected” results of the Women’s Health Initiative investigation of estrogen and estrogen/progestin given to women as hormone replacement at the age of 60 vs the Million Women Study of hormone replacement therapies in the general population. The results of the two epidemiological interventional studies were not comparable but instructive about mechanisms of hormone action in the real world if long-term estrogen deprivation occurs at menopause prior to HRT administration of estrogen alone produces a sustained decrease in breast cancer and the addition of medroxyprogesterone acetate [MPA] not only reverses but increases breast carcinogenesis. (91)

Extensive research on estrogen as a treatment for breast cancer and inducer of apoptosis shows Dr. V. Craig Jordan is quite correct about all the above. (80-91)

How to Blow a Light Bulb

Estrogen deprivation upregulates Estrogen Receptors (ER) in the breast cancer cells, which upon later reintroduction of  estrogen, triggers apoptosis. One can think of this as analogous to blowing a 110 V. light bulb if one mistakenly plugs it  into a 220 V outlet. (17)

In 2021, Dr. Nicole Traphagen did preclinical work on two breast cancer cells lines finding estrogen deprivation leads to ER overexpression and high estrogen receptor activation, which converts estrogen from a growth promoter to a growth suppressor. Dr. Nicole Traphagen found in her preclinical breast cancer models implanted cancer xenografts could be entirely controlled by oscillating between two alternating treatments, estrogen deprivation vs. estrogen treatment, writing:

Herein, we demonstrate that ER [Estrogen Receptor] overexpression confers resistance to estrogen deprivation through ER activation in human ER+ breast cancer cells and xenografts grown in mice. However, ER overexpression and the associated high levels of ER transcriptional activation converted 17b-estradiol from a growth-promoter to a growth-suppressor, offering a targetable therapeutic vulnerability and a potential means of identifying patients likely to benefit from estrogen therapy. Since ER+ breast cancer cells and tumors ultimately developed resistance to continuous estrogen deprivation or continuous 17b-estradiol treatment, we tested schedules of alternating treatments. Oscillation of ER activity through cycling of 17b-estradiol and estrogen deprivation provided long-term control of patient-derived xenografts, offering a novel endocrine-only strategy to manage ER+ breast cancer…Although the anti-cancer effects of estrogens have been known since the 1940s (4), clinical use of estrogen therapy has been limited since the introduction of anti-estrogens that have improved adverse events profile (5, 6). More recent clinical studies have demonstrated that treatment with estrogens [i.e., 17β-estradiol (E2), diethylstilbestrol, or ethinylestradiol] elicits anti-tumor effects in approximately 30% of patients with advanced ER+ breast cancer previously treated with anti-estrogens and/or AIs [Aromatase Inhibitors]. Despite the proven efficacy of estrogen therapy, its clinical use has been hindered by a lack of mechanistic understanding and a predictive biomarker to identify patients likely to benefit from this treatment…Clinical evidence indicates that the patients most likely to benefit from estrogen therapy are post-menopausal (12), suggesting that a period of adaption to low levels of endogenous estrogens increases tumor sensitivity to estrogen therapy…Preclinical studies using MCF-7 cells and the WHIM16 patient-derived xenograft model, as well as a clinical case report, suggest that amplification of the gene encoding ER (ESR1) is associated with therapeutic response to estrogen. Herein, we demonstrate that high ER levels confer resistance to estrogen deprivation and increase estrogen-independent ER activity. These high levels of ER elicit therapeutic responses to E2 [estradiol]…the effects of high ER expression are context-dependent, providing a growth advantage under estrogen deprivation but a disadvantage in E2-replete conditions. High expression of ER is therefore targetable with estrogen therapy, and modulating ER activation by cycling estrogen and estrogen deprivation provides long-term control of tumor growth. (17)

More on Animal Models of Breast Cancer – Dr Lakshmanaswamy Rajkumar

Estrogen and Progesterone Induce a Long-lasting Protective Effect on Mammary Tumorigenesis in Two Genetically Engineered Mouse Models.

As mentioned above, breast cancer researchers have a well known method of inducing breast cancer in animals called the MPA (Medroxyprogesterone) Model of Breast Cancer. MPA is carcinogenic and will induce breast cancer in a mouse. Medroxyprogesterone is a synthetic progestin, which means natural progesterone has been chemically altered to create a carcinogenic “Frankenstein” molecule. These “Frankenstein” progestins do not occur anywhere in nature, nor in the human body. What about natural estrogen and progesterone? Can we use natural hormones like estrogen and progesterone in animals to induce breast cancer? The answer is no, natural estrogen and progesterone is protective, and as mentioned above do not induce breast cancer in animal models when used alone without chemical carcinogens. In fact, estrogen and progesterone are breast cancer protective in animal models. This was studied in 2007 by Dr. Lakshmanaswamy Rajkumar, who evaluated natural estrogen and progesterone in two genetically engineered mouse models of breast cancer, finding short doses of estrogen and progesterone induce long lasting protection from breast cancer formation. The first animal model has a deleted P53 tumor suppressor gene. This is called the p53-null mammary transplant model, causing spontaneous breast cancer in mice. In this model, exposing the mouse for 2 weeks to estrogen and progesterone reduced mammary cancer by 70-80%. The second one is called the HuHER2 transgenic mouse model. These transgenic mice mice develop spontaneous mammary gland tumors within 6 to 12 months. Short-term estradiol or estradiol plus progesterone treatment decreased mammary tumor incidence by 66%. Dr. Lakshmanaswamy Rajkumar writes:

These studies demonstrate that short doses of the hormones estrogen and progesterone induce a long-lasting protective effect on mammary tumorigenesis in two genetically engineered mouse models. (78) (34-42)

Breast Cancer Xenografts into Mice Treated with Natural Hormones- Dr. Rajkumar

In 2014, Drs. Arumugam and Rajkumar performed a series of in-vivo experiments in ovarectomized mice transplanted with human breast cancer cell xenografts (MCF-7 cells). The cancer cells were “transfected” with the human aromatase enzyme which converts testosterone to estrogen, meaning the cancer cells are now able to make their own estrogen. After xenografting of human cancers, the mice were treated with various combinations of natural hormones, estrogen, progesterone, testosterone and DHEA. Dr. Rajkumar found the natural hormone treated mice had maximum reduction in tumor growth, and better outcomes than the AI (aromatase inhibitor) treated mice, writing:

Because estrogen-blocking aromatase inhibitors are the current adjuvant treatment after hormone-sensitive breast cancer, common sense would lead to the assumption that any treatment containing estrogen itself would lead to opposite, highly negative impact on tumor growth. However, this turned out not to be the case. As was the case for general health markers, maximal reduction in tumor growth was achieved by E [estrogen] plus P [progesterone] plus T [testosterone] treatment….current standard of practice considers hormones of any type absolutely contraindicated after hormone-receptor-positive breast cancer, with the assumption being that hormones “throw fuel on the fire” of cancer.  This assumption makes intuitive sense, since current treatment is to block remaining estrogens with aromatase inhibitors, the exact opposite…Our results thus did not confirm the “throwing fuel on the fire” conception prevalent among clinicians….In summary, our results indicate that the use of appropriate combinations of natural hormones along with, or instead of, classical breast cancer treatments [aromatase inhibitors] is beneficial against postmenopausal symptoms and improves cardiac and osteoporotic health in the mouse model. The natural hormone combinations tested in this study provide evidence for a better alternative to standard aromatase inhibitor treatment following breast cancer in women. (100)

Adding Aromatase Inhibitor Increases Recurrence

In the above study and quote, Dr. Rajkumar suggests adding an Aromatase Inhibitor Drug (AI) to post-menopausal HRT. This was examined in 2022 by Dr. Søren Cold from Denmark with an observational cohort study of 8461 women post a breast cancer diagnosis. Of the 8461, 1,957 women used vaginal estrogen therapy (VET) and 133 used menopausal hormone therapy (MHT). The cohort was followed 9.8 years for recurrence and 15.2 years for mortality. The overall mortality was decreased by 22 percent for VET and 6 percent for MHT. Dr. Cold found no increased recurrence in the VET or MRT groups. However, in women receiving VET or MRT and also receiving adjuvant AI drug, breast cancer recurrence was increased by 39% compared to non-users. These findings suggest better outcome is achieved without adding adjuvant AI drugs to HRT for breast cancer survivors, thus answering the above question by Dr. Rajkumar. Dr. Cold writes:

In postmenopausal women treated for early-stage estrogen receptor–positive BC, neither VET nor MHT was associated with increased risk of recurrence or mortality. A subgroup analysis revealed an increased risk of recurrence, but not mortality, in patients receiving VET with adjuvant aromatase inhibitors. (101)

Breast Cancer Models in Mice – Estrogen Does Not Induce Breast Cancer

If estrogen causes breast cancer, one would think that treating mice with estrogen would induce breast cancer. This was studied in 2021 by Dr. Chong Liu who reviewed the various breast cancer models in mice finding the simple administration of estrogen to a wild type mouse was insufficient to create a viable model of breast cancer. The mouse models for breast cancer required a genetically engineered mouse or the use of carcinogenic chemicals.(107)

A Well Designed Bioidentical Program

A well designed bioidentical hormone program will decrease the risk for breast cancer. For post menoppausal women having natural or drug induced LTED (long term estrogen depreletion), estrogen induces apoptosis in latent breast cancer cells having upregulated ER (estrogen receptors) due to estrogen deprivation. The 18 year follow up of the WHI second arm (premarin alone) showed a 45 percent reduction in mortality from breast cancer in the estrogen treated group (CEE, horse estrogen), compared to placebo. Of course, for women who have intact uterus, hormone replacement with estrogen always includes progesterone for endometrial protection. Although breast cancer survivors will benefit from hormone replacement, estrogen is one of many growth factors for breast cancer (and many other cancers), so it is not advisable to give estrogen to women with active cancer, unless of course, they have been treated for a time with estrogen blocking drugs (Tamoxifen or aromatase inhibitors), and their cancer has become resistant to the estrogen-blocking drug. This mimics a period of estrogen deprivation, and the cancer cells are now ripe for apoptosis induced by estrogen. However, this type of oscillating breast cancer treatment should be done under the care of an experienced integrative oncologist. For more on this, see the article: Hormone Replacement for Breast Cancer Survivors. For a review of the many health benefits of natural bioidentical hormone replacement. see: Menopausal Hormone Replacement Health Benefits

Conclusion: Thanks and credit goes to Dr. Lindsay Berkson for bringing to my attention the above re-analysis of the WHI by Dr. Hodis, who points out the placebo group included women with prior hormone use which confers protection from breast cancer and gives the false impression of increased breast cancer risk in the Premarin+ MPA group compared to placebo. When prior hormone use is removed from the placebo group, trend lines for breast cancer are superimposed for both groups (left chart Fig.1)

Articles with Related Interest

Link to my Free e-Book Bioidentical Hormones 101

All Bioidentical Hormone Articles by Jeffrey Dach MD

The Safety of Transdermal Estrogen Part One

The Safety of Transdermal Estrogen vs. Oral Estrogen Part Two

Jeffrey Dach MD
7450 Griffin Road Suite 180/190
Davie, Fl 33314
954-792-4663

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image: The Scream by Annemarie Busschers, painting, 250 x 160 cm 2010 private collection Miami, courtesy of Wikimedia Commons.

References:

1) Manson, JoAnn E., et al. “Menopausal hormone therapy and long-term all-cause and cause-specific mortality: the Women’s Health Initiative randomized trials.” JAMA 318.10 (2017): 927-938.

2) Hodis, Howard N., and P. M. Sarrel. “Menopausal hormone therapy and breast cancer: what is the evidence from randomized trials?.” Climacteric 21.6 (2018): 521-528.

Women’s Health Initiative

Compared with women who received placebo, women in the WHI-CEE trial showed a 21% (Hazard ratio [HR], 0.79; 95% confidence interval [CI], 0.61–1.02) non-significant reduction in breast cancer risk after a median 7.2 years of randomized treatment, with 7 fewer cases of invasive breast cancer/10,000 women/year of CEE therapy (4).

Women who were actually taking their study pills and were at least 80% compliant with CEE therapy, breast cancer risk was statistically significantly reduced by 32% (HR, 0.67; 95% CI, 0.47–0.97) relative to placebo (5).

In addition, across all women regardless of compliance status, ductal carcinoma was statistically significantly reduced by 29% (HR, 0.71; 95% CI, 0.52–0.99) by CEE therapy relative to placebo after a mean 7.1 years of randomized treatment (5).

After a mean 10.7 years of follow-up (including a mean 7.1 years of intervention), breast cancer risk assessed across all women regardless of compliance status was statistically significantly reduced by 23% (HR, 0.77; 95% CI, 0.62–0.95) in women originally randomized to CEE therapy relative to placebo (6).

A non-significant reduction in breast cancer of 20% (HR, 0.80; 95% CI, 0.58–1.11) was evident after a median 13.2 years of follow-up (including a median 7.2 years of intervention) in those women originally randomized to CEE therapy relative to those randomized to placebo (4).

After 18 years of cumulative follow-up of the WHI-CEE cohort, breast cancer mortality was statistically significantly reduced by 45% (HR, 0.55; 95% CI, 0.33–0.92). This may well be the most significant and most over-looked finding of the WHI-CEE trial (7).

3) Long-term Follow-up Shows Estrogen Alone and Estrogen Plus Progestin Have Opposite Effects on Breast Cancer Incidence in Postmenopausal Women by Rowan Chlebowski, Dec. 13, 2019

After 16.1 years of cumulative follow-up, among those who received CEE alone, there were 520 incident breast cancers during the post-intervention period. Compared with women who had received placebo, those who had received CEE [Premarin] were 23 percent less likely to have been diagnosed with breast cancer and 44 percent less like to die from the disease, and these positive outcomes are in agreement with the earlier findings from this trial during the intervention period…After 18.3 years of cumulative follow-up, among those who received CEE plus MPA, there were 1,003 incident breast cancers during the post-intervention period. Compared with women who had received placebo, those who had received CEE plus MPA were 29 percent more likely to have been diagnosed with breast cancer…

4) Substack article by Dr. Lindsay Berkson on Estrogen Hormone Replacement for Menopausal Women, a rebuttal to Mercola. Dr lindsay devaki berkson Oct 24, 2023

estrogen “protects” healthy breast tissue from getting breast cancer in the first place. And, if a women has been on estrogen therapies for an average of 5 years and then gets breast cancer, the estrogen therapies “reduce” her risk of dying from breast cancer by 44%. Nothing else like estrogen therapies has ever been shown to be so breast protective.

5) Siddique, Y. H., and M. Afzal. “A review on the genotoxic effects of some synthetic progestins.” Int J Pharmacol 4.6 (2008): 410-30.

6) The Anticancer Testosterone Metabolite 3β-Adiol. Published in: Townsend Letter By. Dr. Jonathan V. Wright, MD  The bad side is that too much 16-OHE1 increases breast and prostate cancer risk.11-14 But like DHT, which also increases cancer risk, 16a-OHE1 s transformed into the anticarcinogenic

7) Warner, Margaret, et al. “25 years of ERβ: a personal journey.” Journal of Molecular Endocrinology 68.1 (2022): R1-R9.

8) Rymbai, Emdormi, et al. “Role of estrogen receptors in cancer: a special emphasis on the therapeutic potential of estrogen receptor ß.” Pharmaceutical Sciences Asia 49.5 (2022).

9) Wu, Wan-fu, et al. “Estrogen receptor β and treatment with a phytoestrogen are associated with inhibition of nuclear translocation of EGFR in the prostate.” Proceedings of the National Academy of Sciences 118.13 (2021): e2011269118.

10) Chimento, Adele, et al. “Estrogen receptors-mediated apoptosis in hormone-dependent cancers.” International journal of molecular sciences 23.3 (2022): 1242.

11) free pdf
Vasconsuelo, Andrea, et al. “Role of 17β-estradiol and testosterone in apoptosis.” Steroids 76.12 (2011): 1223-1231.

17b-Estradiol (E2) and Testosterone (T) exert actions in most animal tissues, in addition to the reproductive system. Thus, both sex steroid hormones affect growth and different cell functions in several organs. Accordingly, the nuclear estrogen (ER) and androgen (AR) receptors are ubiquitously expressed. Moreover, ER and AR may have non-classical intracellular localizations, e.g. plasma membrane, mitochondria and endoplasmic reticulum, raising additional complexity to the functional roles of E2 and T. In addition to the modulation of gene transcription by direct interaction with their cognate nuclear receptors, the steroids can rapidly activate signaling pathways by a non-genomic mechanism mediated by receptors identical to or different from known steroid receptors. Among various functions, E2 and T can regulate apoptosis through those pathways. In mitochondria, the presence of ER and AR and actions of estrogen and androgen have been shown, in keeping with the organelle being a control point of apoptosis. The most recurrent action for each steroid hormone is the protection of mitochondria against different insults, resulting in antiapoptosis. This review summarizes the molecular basis of the modulation of programmed cell death by E2 and T in several tissues.

12) Vasconsuelo, Andrea, et al. “Role of 17β-estradiol and testosterone in apoptosis.” Steroids 76.12 (2011): 1223-1231.

However, under some specific conditions E2 could trigger apoptosis in breast cancer cells, opposed to its well studied antiapoptotic role. This peculiar hormone behavior has been observed in cells from breast cancer which have been long term estrogen-deprived (LTED) or treated exhaustively with antiestrogens [87]. Curiously, the paradoxical induction of apoptosis by estrogen has been established under several unusual circumstances. For example, in this case, the pre-conditions of prolonged estrogen depletion or exhaustive treatment with anti-estrogens of the breast cancer cells are mandatory requisites to trigger apoptosis by E2 and could explain the dual action of the steroid to stimulate growth or apoptosis. Thus, the development of antihormone resistance over years of therapy, reprograms the survival mechanism of the breast cancer cell so that estrogen no longer functions as a survival factor but as a death signal.

13) Rizza, Pietro, et al. “Estrogen receptor beta as a novel target of androgen receptor action in breast cancer cell lines.” Breast cancer research 16 (2014): 1-13.

The two isoforms of estrogen receptor (ER) alpha and beta play opposite roles in regulating proliferation and differentiation of breast cancers, with ER-alpha mediating mitogenic effects and ER-beta acting as a tumor suppressor. Emerging data have reported that androgen receptor (AR) activation inhibits ER-positive breast cancer progression mainly by antagonizing ER-alpha signaling. However, to date no studies have specifically evaluated a potential involvement of ER-beta in the inhibitory effects of androgens.

Collectively, these data provide evidence for a novel mechanism by which activated AR, through an up-regulation of ER-beta gene expression, inhibits breast cancer cell growth.

14) Pietri, Elisabetta, et al. “Androgen receptor signaling pathways as a target for breast cancer treatment.” Endocrine-related cancer 23.10 (2016): R485-R498.

15) Hickey, Theresa E., et al. “The androgen receptor is a tumor suppressor in estrogen receptor–positive breast cancer.” Nature medicine 27.2 (2021): 310-320.

Notably, AR agonists combined with standard-of-care agents enhanced therapeutic responses. Mechanistically, agonist activation of AR altered the genomic distribution of ER and essential co-activators (p300, SRC-3), resulting in repression of ER-regulated cell cycle genes and upregulation of AR target genes, including known tumor suppressors. A gene signature of AR activity positively predicted disease survival in multiple clinical ER-positive breast cancer cohorts. These findings provide unambiguous evidence that AR has a tumor suppressor role in ER-positive breast cancer and support AR agonism as the optimal AR-directed treatment strategy, revealing a rational therapeutic opportunity.

16) You, Chan-Ping, et al. “Modulating the activity of androgen receptor for treating breast cancer.” International Journal of Molecular Sciences 23.23 (2022): 15342.

17) Traphagen, Nicole A., et al. “High estrogen receptor alpha activation confers resistance to estrogen deprivation and is required for therapeutic response to estrogen in breast cancer.” Oncogene 40.19 (2021): 3408-3421.

Herein, we demonstrate that ER overexpression confers resistance to estrogen deprivation through ER activation in human ER+ breast cancer cells and xenografts grown in mice. However, ER overexpression and the associated high levels of ER transcriptional activation converted 17b-estradiol from a growth-promoter to a growth-suppressor, offering a targetable therapeutic vulnerability and a potential means of identifying patients likely to benefit from estrogen therapy. Since ER+ breast cancer cells and tumors ultimately developed resistance to continuous estrogen deprivation or continuous 17b-estradiol treatment, we tested schedules of alternating treatments. Oscillation of ER activity through cycling of 17b-estradiol and estrogen deprivation provided long-term control of patient-derived xenografts, offering a novel endocrine-only strategy to manage ER+ breast cancer.

Although the anti-cancer effects of estrogens have been known since the 1940s (4), clinical use of estrogen therapy has been limited since the introduction of anti-estrogens that have improved adverse events profile (5, 6). More recent clinical studies have demonstrated that treatment with estrogens [i.e., 17β-estradiol (E2), diethylstilbestrol, or ethinylestradiol] elicits anti-tumor effects in approximately 30% of patients with advanced ER+ breast cancer previously treated with anti-estrogens and/or AIs (7–11). Despite the proven efficacy of estrogen therapy, its clinical use has been hindered by a lack of mechanistic understanding and a predictive biomarker to identify patients likely to benefit from this treatment.

Clinical evidence indicates that the patients most likely to benefit from estrogen therapy are post-menopausal (12), suggesting that a period of adaption to low levels of endogenous estrogens increases tumor sensitivity to estrogen therapy.

Preclinical studies using MCF-7 cells and the WHIM16 patient-derived xenograft model, as well as a clinical case report, suggest that amplification of the gene encoding ER (ESR1) is associated with therapeutic response to estrogen (13–15). Herein, we demonstrate that high ER levels confer resistance to estrogen deprivation and increase estrogen-independent ER activity. These high levels of ER elicit therapeutic responses to E2.

the effects of high ER expression are context-dependent, providing a growth advantage under estrogen deprivation but a disadvantage in E2-replete conditions. High expression of ER is therefore targetable with estrogen therapy, and modulating ER activation by cycling estrogen and estrogen deprivation provides long-term control of tumor growth.

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18) presented at the yearly SA TX Breast Cancer Symposium see below including authors at 2019 SABCS.

Long-term Follow-up Shows Estrogen Alone and Estrogen Plus Progestin Have Opposite Effects on Breast Cancer Incidence in Postmenopausal Women by Rowan Chlebowski, Dec. 13, 2019

Estrogen alone decreased, while adding progestin increased, breast cancer incidence
SAN

CEE-alone and CEE plus MPA use have opposite effects on breast cancer incidence. CEE alone significantly decreases breast cancer incidence which is long term and persists over a decade after discontinuing use. CEE plus MPA use significantly increases breast cancer incidence which is long term and persists over a decade after discontinuing use. As a result of the attenuation of subgroup interactions: all postmenopausal women with prior hysterectomy using CEE-alone have the potential benefit of experiencing a reduction in breast cancer incidence while all postmenopausal women using CEE plus MPA have the potential risk of experiencing an increase in breast cancer incidence.

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!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!! BEST !!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!

19) Hodis, Howard N., and P. M. Sarrel. “Menopausal hormone therapy and breast cancer: what is the evidence from randomized trials?.” Climacteric 21.6 (2018): 521-528.

The relationship between menopausal hormone therapy (HT) and breast cancer is complex and further complicated by misinformation, perception, and overgeneralization of data. These issues are addressed in this mini-review through the lens of the Women’s Health Initiative (WHI) that has colored the view of HT and breast cancer. In the WHI, unopposed conjugated equine estrogen (CEE) reduced breast cancer risk and mortality. In the WHI CEE plus continuously combined medroxyprogesterone acetate (MPA) trial, although the hazard ratio (HR) was elevated it was statistically non-significant for an association between CEE + MPA and breast cancer. In fact, the increased HR was not due to an increased breast cancer incidence rate in women randomized to CEE + MPA therapy but rather due to a decreased and unexpectedly low breast cancer rate in the subgroup of women with prior HT use randomized to placebo. For women who were HT naïve when randomized to the WHI, the breast cancer incidence rate was not affected by CEE + MPA therapy relative to placebo for up to 11 years of follow-up. The current state of science indicates that HT may or may not cause breast cancer but the totality of data neither establish nor refute this possibility. Further, any association that may exist between HT and breast cancer appears to be rare and no greater than other medications commonly used in clinical medicine.

any conclusions that HT causes breast cancer has eluded definitive proof for over 5 decades, including WHI.

However, the data clearly show that CEE+MPA therapy had a null effect on breast cancer risk particularly in the subgroup of women representing the typical population of women treated with HT who are HT naïve before receiving menopausal HT.

SEE FIGURE 1 !!!!!!!!!!!!!!!!!!!!!

Although the cause of this outlier low incidence rate of breast cancer in the placebo group of women who had prior HT use is unknown, it is stunning that this unappreciated fact has escaped a more conspicuous and transparent discussion of the important impact that this finding has on interpretation of the breast cancer results from the WHI-CEE+MPA trial.

it is clear that breast outcome data from the WHI-CEE+MPA trial has been misinterpreted and overgeneralized

That is, the WHI-CEE+MPA trial strongly refutes the possibility that CEE+MPA therapy increased the risk of breast cancer in this trial.

50 years of study has failed to conclusively prove cause-and-effect between HT and breast cancer with the preponderance of evidence supporting benefits over risks with amelioration of downstream morbidity and mortality.

!!!!!!!!!!!!!!!!!! ???????? !!!!!!!!

After 18 years of cumulative follow-up of the WHI-CEE cohort, breast cancer mortality was statistically significantly reduced by 45% (HR, 0.55; 95% CI, 0.33–0.92). This may well be the most significant and most over-looked finding of the WHI-CEE trial (7).

20) Manson, JoAnn E., et al. “Menopausal hormone therapy and long-term all-cause and cause-specific mortality: the Women’s Health Initiative randomized trials.” Jama 318.10 (2017): 927-938.

cumulative 18-year follow-up,

2 randomized clinical trials between 1993 and 1998 and followed up through December 31,2014

Breast Cancer Mortality

CEE plus MPA vs Placebo active=61/ Placebo=40 HR=1.44

CEE alone vs Placebo
active=22 /Placebo 41 HR 0.55

cumulative 18-year follow-up of WHI
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21) Mercola & Guest’s Analysis – WRONG on Estrogen By Devaki Berkson Oct 24, 2023 Substack

Dr. Lindsay Berkson:

The WHI 1 authors forgot to ask, and thus did not remove, in the placebo group, any women who had already taken estrogen therapies.

Since estrogen was ultimately, on re-analysis found to be “breast protective” , and the synthetic progestins were huge adverse contributing issues, this made the incidence of breast cancer in the placebo group of ladies, lower, as women had already taken the protective estrogen.

This made the experimental arm, women taking hormones, falsely appear as though they had more cases of breast cancer.

When the data was re-analyzed, thus “righted” by taking out this “confounding issue”, and longer term effects of estrogen looked at with a fine tooth comb, the same original authors, re-published their re-analysis. This is now what I call the WHI 2.

Conclusions of WHI 2:

Women taking estrogen replacement therapy (ERT) had 23% less incidence or chance of getting breast cancer in the first place.

And if you had been on ERT, and got breast cancer, you had a 44% decreased chance of dying from it.

Progestins were more the breast damaging issue. Not estrogen.

So, stunning as it is, being on ERT put you in a better position, even if you went on to get breast cancer! This is something that is now replicated. Substantiated. But not taught in most med schools or appreciated by most docs and women. Or lawyers!

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21) Baik, Seo H., Fitsum Baye, and Clement J. McDonald. “Effects of Hormone Therapy on survival, cancer, cardiovascular and dementia risks in 7 million menopausal women over age 65: a retrospective observational study.” medRxiv (2022): 2022-05.

The 7 million menopause study

The 7 million NIH study, the largest study ever run on women, with 1.5 million American women on ERT, shows that women 65 and older on estrogen therapies have statistically “less” of all 5 cancers studied (breast, ovarian, uterine, lung and colon). As well as live almost 20% longer, healthier lives. With less heart disease (unless on oral estrogens) and less dementias.

The Arizona insurance study showed that women (almost 400,000) taking natural steroids had 79% less dementias (Association between menopausal hormone therapy and risk of neurodegenerative diseases: Implications for precision hormone therapy. Alzheimers Dement (N Y). 2021 May 13;7(1):e12174.).

22) https://pubmed.ncbi.nlm.nih.gov/34027024/
Kim, Yu Jin, et al. “Association between menopausal hormone therapy and risk of neurodegenerative diseases: Implications for precision hormone therapy.” Alzheimer’s & Dementia: Translational Research & Clinical Interventions 7.1 (2021): e12174.

23) Evaluating Estrogen Detoxification to Understand Breast Cancer Risk
by Debbie Rice, ND, MPH
The most dangerous estrogen metabolite is the 4-OH-E1 metabolite.The 4-OH-E1 metabolite has the potential to become a reactive quinone that causes DNA damage. Thus, if the body is not able to neutralize the 4-OH metabolites well or efficiently, they can wreak havoc on DNA. When DNA is damaged, it disrupts cellular signaling and the body’s ability to repair itself and stop abnormal cell growth. There is correlation between increased 4-OH-E1 metabolites and breast cancer risk. Miao, et al state: “Among many alterations of sex hormone metabolisms, 4-hydroxy estrogen (4-OH-E) metabolite was found to be significantly increased in the urine samples of patients with breast cancer compared with the normal healthy controls. This was the most important risk factor for breast cancer”.

24) Does Estrogen Cause Breast Cancer ? The Answer is –
NO – Estrogen Does NOT Cause Breast Cancer by Jeffrey Dach MD
The results of the 11 year follow up of the Women’s Health Initiative was covered in my previous article.(1) Rather than causing breast cancer, estrogen prevented it. This study found a significant reduction in breast cancer rates for Post-Menopausal women using Estrogen Replacement (Premarin Only Arm)(To be exact, there was a 23% reduction in breast cancer in Premarin Users compared to placebo.)(1)

25) Rebuttal to Mercola’s Article on Hormone Therapy Lindsey Berkson, DC

Women taking estrogen replacement therapy (ERT) had 23% “less” incidence or chance of getting breast cancer in the first place…And if you had been on ERT and got breast cancer, you had a “44%” decreased chance of dying from it.
Progestins were the more breast-damaging issue. Not estrogen.

26) The True Power of Hormones: An Interview with Devaki Lindsey Berkson, DC by Steven Schindler / October 13, 2023
Price-Pottenger’s former executive director, Steven Schindler, on the important role of hormones in helping us achieve our highest possible levels of health and vitality.

27) Podcast with Dr Anna Cabeca and Dr. Lindsay Berkson discussing the myths surrounding Estrogen and HRT for women. The Girlfriend Doctor w/ Dr. Anna Cabeca. Hormones and Breast Cancer with Dr. Devaki Lindsey Berkson
Dr. Anna Cabeca, the girlfriend doctor podcast. Importance of hippocampus volume. 20 years after the WHI Trial.

Dr Lindsay Berkson Austin Texas
1977 Rotation in integrative medicine with Dr. Jonathan Wright. In practice for 52 years. My Current Age 75.

Dr Wright taught hormones and gut health were the most important. He had heidelberg capsule anaysis machine to test stomach acid production.

I wrote Hormone Deception about endocrine disruption. Basded on that book, I was invited to an estrogen think tank, and work as a distinuished estrogen scholar at Tulane Med SChool under John Mcclaughlin as my mentor. Worked with the scientists who discovered the first estrogen receptors. Jensen and Gustafson.

Women’s hormones are the most controversial and confusing topic in medicine today.

Most women are terrified of hormones, and really think estrogen is really a bad thing. This term estrogen dominance dominated the airways/ Lets have a conversation to clear some of this up.

very few doctors have heard of the re-analysis of the womens health initiative,

A big part of anti-aging comes from hippocamus volume. This is where memories and emotions, motivation, soul resides in brain. Hippocampus shrinks as we age.
Exercise and meditation does not preserve volume. However, HRT does preserve it.
Yale MedX study tracked volume of hippocampus.
Studies 20 years ago from McGill U by Catherine Lonhartford showed HRT restores hippocampus volume.

re-analysis of whi

peter attia
leon speroff said

28) Testosterone is Breast Cancer Preventive: Mechanism of Action by Jeffrey Dach MD
There are two estrogen receptors, Alpha and Beta. The Alpha receptor is pro-carcinogenic. The Beta Receptor is protective and suppresses carcinogenesis. Estradiol attached to both receptors 50:50. Estrone (E1) attaches mostly to ER-alpha, while Estriol (E3) attached mosty to ER Beta (protective). The most like likely mechanism for testosterone’s protective effect in breast cancer prevention is the testosterone metabolite 3β-Adiol which attaches to Estrogen Receptor Beta (ER-Beta), thus upregulated ER-Beta expression, thus inhibiting breast cancer cell growth.(38-49)
This is illustrated in 2014 by Dr. Pietro Rizzo who writes:
The two isoforms of estrogen receptor (ER) alpha and beta play opposite roles in regulating proliferation and differentiation of breast cancers, with ER-alpha mediating mitogenic effects and ER-beta acting as a tumor suppressor. …..Collectively, these data provide evidence for a novel mechanism by which activated AR [Androgen Receptor], through an up-regulation of ER-beta gene expression, inhibits breast cancer cell growth.(45) Emphasis Mine.

Screening Mammograms Do NOT Reduce Overall Mortality

29) Esserman, Laura, Yiwey Shieh, and Ian Thompson. “Rethinking  screening for breast cancer and prostate cancer.” JAMA 302.15 (2009): 1685-1692.

30) Kowalski, Amanda E. “Mammograms and mortality: how has the evidence evolved?.” Journal of Economic Perspectives 35.2 (2021): 119-140.

31) Rethink the monies spent on cancer screening tests November 24, 2023 by Erik Peper: Following is a summary of Bretthauer et al. (2023) findings: The only cancer screening with a significant lifetime gain (approximately 3 months) was sigmoidoscopy. There was no significant difference between harms of screening and benefits of screening for: mammography prostate cancer screening.  FOBT (fecal occult blood test) screening every year or every other year lung cancer screening Pap test cytology for cervical cancer screening, no randomized clinical trials with cancer-specific or all-cause mortality end points and long term follow-up were identified.

32) Bretthauer, Michael, et al. “Estimated lifetime gained with cancer screening tests: a meta-analysis of randomized clinical trials.” JAMA Internal Medicine 183.11 (2023): 1196-1203.
Conclusions and Relevance: The findings of this meta-analysis suggest that current evidence does not substantiate the claim that common cancer screening tests save lives by extending lifetime, except possibly for colorectal cancer screening with sigmoidoscopy.

33) Autier, Philippe, et al. “Breast cancer mortality in neighbouring European countries with different levels of screening but similar access to treatment: trend analysis of WHO mortality database.” Bmj 343 (2011).

Conclusions The contrast between the time differences in implementation of mammography screening and the similarity in reductions in mortality between the country pairs suggest that screening did not play a direct part in the reductions in breast cancer mortality.

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34) Lakshmanaswamy, Rajkumar. Approaches to understanding breast cancer. Vol. 151. Academic Press, 2017.

35) Arumugam, Arunkumar, Elaine A. Lissner, and Rajkumar Lakshmanaswamy. “The role of hormones and aromatase inhibitors on breast tumor growth and general health in a postmenopausal mouse model.” Reproductive Biology and Endocrinology 12 (2014): 1-13.

36) Arumugam, Arunkumar, et al. “Short-term treatment with pregnancy levels of estradiol prevents breast cancer by delaying promotion and progression.” Cancer Research 73.8_Supplement (2013): 199-199.

We have earlier demonstrated that short-term treatment with pregnancy levels of estradiol (STET) is very effective in preventing mammary carcinogenesis. Rats were injected with N-methyl-N-nitrosourea at 7 weeks of age and divided into 2 groups. Short-term treatment with pregnancy levels of estradiol drastically reduced the incidence of overt mammary cancers. …The transplantation experiment indicated that the progression of LMMC [latent microscopic mammary cancers] was dependent on the systemic environment it is exposed to. The LMMC derived from control were not able to progress further to make overt cancers when transplanted STET hosts, while the LMMC derived from STET were able to progress to overt cancers when transplanted to control hosts. These findings demonstrate that STET confers protection against mammary cancer development by blocking promotion and progression of transformed cells.

37) Lakshmanaswamy, Rajkumar, Raphael C. Guzman, and Satyabrata Nandi. “Hormonal prevention of breast cancer: significance of promotional environment.” Hormonal Carcinogenesis V. New York, NY: Springer New York, 2008. 469-475.

38) Rajkumar, Lakshmanaswamy, et al. “Hormone-induced protection of mammary tumorigenesis in genetically engineered mouse models.” Breast Cancer Research 9 (2007): 1-11.

39) Nandi, Satyabrata, et al. “Estrogen can prevent breast cancer by mimicking the protective effect of pregnancy.” Hormonal Carcinogenesis IV (2005): 153-165.

40) Rajkumar, Lakshmanaswamy, et al. “Prevention of mammary carcinogenesis by short-term estrogen and progestin treatments.” Breast Cancer Research 6.1 (2003): 1-7.

41) Rajkumar, Lakshmanaswamy, et al. “Short-term exposure to pregnancy levels of estrogen prevents mammary carcinogenesis.” Proceedings of the National Academy of Sciences 98.20 (2001): 11755-11759.

42) Guzman, Raphael C., et al. “Hormonal prevention of breast cancer: mimicking the protective effect of pregnancy.” Proceedings of the National Academy of Sciences 96.5 (1999): 2520-2525.

======================================== =

Adriane Fugh-Berman Menopause

43) The Truth about Hormone Replacement Therapy : How to Break Free from the Medical Myths of Menopause by Adrienne Fugh-Berman and National Women’s Network Staff (2002, Trade Paperback)

Just Say No to America’s Number-One Drug Menopause is not a disease.So why are millions of American women taking a drug for this natural body process? The widespread popularity of hormone replacement therapy (HRT) is a triumph of marketing and advertising over science. Although HRT and estrogen replacement therapy (ERT) can help some women with certain menopause-related problems, the benefits have been oversold to women and their health care providers. There is no scientifically valid evidence that estrogen prevents heart disease, colon cancer, or Alzheimer’s. Nor is there any evidence that it keeps you looking younger, preserves your sex drive, or enhances your memory. However, HRT does carry the risk of serious side effects, including certain cancers. Should you be taking such risky drugs to help you get through menopause?

44) Menopause is not a disease.  December 10, 2023 by Her Turn News

Here’s a news ‘hot flash’ for you: menopause is not a disease. Menopause is not a disability — but you might think so if you’ve been paying attention to the new marketing push targeting mid-life women. We have a feminist take on the natural process for mid-life women. Her Turn reporter Arlene Zaucha talks to a longtime feminist health activist Dr, Adriane Fugh Berman about the issue. Dr. Fugh Berman runs Pharmed Out, which has more information at pharmedout.org.

Errors

1) There is no medical test for menopause.

Marked elevation of LH and FSH hormones indicates menopausual state characterized by ovarian failure and low estrogen levels.

The only symptoms proven to be associated with menopause is hot flashes and night sweats and vaginal dryness. Most menopausal symptoms are the result of aging. In Japan, menopause is associated with joint pain.

estrogen deficiency also causes joint pain, osteoarthritis, bone loss, osteoporosis, increased fracture risk, insomnia, loss of libido, vaginal atrophy and vulvo-vaginal syndrome.
(chronic UTI’s)

estrogen alone resulted in endometrial cancer. This is correct

Later on , hormones came back with a progestin added. This was meant to prevent heart disease, stroke, dementia. All things we now know hormones dont health and in fact increase.

Dr Fugh-Berman’s error is lumping together Progestins with progesterone, and not differentiating between the two. The progestins are the cause of poor health outcomes, while human bioidentical hormones estrogen are associated with good health outcomes.

HERS Trial tested hormones in women who had had a heart attack. It was found there was no beneficial effect at al.

WHI clinical trial NIH funded under Bernadine Healy. This trial found the risks far outweigh the benefit for menopausal hormone therapy.

Again, Dr Fugh-Berman fails to recognize the poor outcomes were from use of synthetic progestins in the WHI.

Error: “In terms of disease prevention, Hormones should never be used for disease prevention.” This is wrong. Bioidentical Hormones, estrogen, progesterone, testosterone are used and should be used to prevent estrogen deficiency diseases of osteoarthritis, osteoproosis, heart disease, and dementia, macular degeneration and cancer prevention.

“Women should stop HRT when hot flashes stop.” This is an error.

Error:”Estrogen increases blood clots” Oral estrogen does,. Transdermal does not. Failure to say transdermal estrogen does not increase blood clots and is preferred over oral estrogen.

New York times criticized the WHI study.

“all these ctiticisms are from the industry?

Error: Dr Fugh-Berman fails to recognize and mention the postive health outcomes of the 2nd arm (premarin alone) WHI study.

Error: “This idea that breast cancer risk is low. There is really no question that hormone therapy increases breast cancer risk.
Dr Fugh-Berman fails to recognize and mention the reduction in breast cancer in the premarin alone group. And the increased breast cancer in the progestin users.

Error: if you are not having hot flashes, you dont need medication of any sort.

Error: Symptoms associated with menopasue are not caused by menopause. They are caused by aging.

Medicalization of menopause is an industry funded campaign.

Error: Low doses of antidepressant can be helpful in menopause.

Error: phytoestrogens in soybeans can be helful for menopausal symptoms.

Error: Hormones dont work for everyone either.

Error: Vaginal dryness can be dealt with moisturizers or topical estrogen.

free pdf

44B) Fugh-Berman, Adriane. “The science of marketing: How pharmaceutical companies manipulated medical discourse on menopause.” Women’s Reproductive Health 2.1 (2015): 18-23.

The case is closed. Women without symptoms should not use HT [hormones therapy]. Women with symptoms should carefully weigh benefits against risks, and, if they choose to take hormones, they should take as little as possible for as short a time as possible.

 

!!!!!!!!!!!!!!!!!!!!!  GOOD  !!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!

estrogen is evil !!!!

44C) Fugh-Berman, Adriane, and Anthony R. Scialli. “Gynecologists and estrogen: an affair of the heart.” Perspectives in biology and medicine 49.1 (2006): 115-130.

=====================================
The Estrogen Paradox

45) Chlebowski, Rowan T., et al. “Randomized trials of estrogen-alone and breast cancer incidence: a meta-analysis.” Breast cancer research and treatment.

10 randomized trials included 14,282 participants and 591 incident breast cancers.
For 5 trials evaluating estradiol formulations, RR = 0.63 95% CI 0.34-1.16, P = 0.15.
Conclusion: The totality of randomized clinical trial evidence supports a conclusion that estrogen-alone use significantly reduces breast cancer incidence.

46) Abderrahman, Balkees, and V. Craig Jordan. “Estrogen for the treatment and prevention of breast cancer: a tale of 2 Karnofsky lectures.” The Cancer Journal 28.3 (2022): 163-168.

47) Jordan, V. Craig. “The new biology of estrogen-induced apoptosis applied to treat and prevent breast cancer.” Endocrine-related cancer 22.1 (2015): R1-R31.

The successful use of high dose synthetic estrogens to treat post-menopausal metastatic breast cancer, is the first effective “chemical therapy” proven in clinical trial to treat any cancer. This review documents the clinical use of estrogen for breast cancer treatment or estrogen replacement therapy (ERT) for postmenopausal hysterectomized women which can either result in breast cancer cell growth or breast cancer regression. This has remained a paradox since the 1950s until the discovery of the new biology of estrogen induced apoptosis at the end of the 20th century. The key to triggering apoptosis with estrogen is the selection of breast cancer cell populations that are resistant to long term estrogen deprivation. However, through trial and error estrogen independent growth occurs. At the cellular level, estrogen induced apoptosis is dependent upon the presence of the estrogen receptor (ER) which can be blocked by non-steroidal or steroidal anti-estrogens. The shape of an estrogenic ligand programs the conformation of the ER complex which in turn can modulate estrogen induced apoptosis: class I planar estrogens (eg: estradiol) trigger apoptosis after 24 hours whereas class II angular estrogens (eg: bisphenol triphenylethylene) delay the process until after 72 hours. This contrasts with paclitaxel that causes G2 blockade with immediate apoptosis. The process is complete within 24 hours. Estrogen induced apoptosis is modulated by glucocorticoids and cSrc inhibitors but the target mechanism for estrogen action is genomic and not through a non-genomic pathway. The process is step wise through the creation of endoplasmic reticulum stress and, inflammatory responses that then initiate an unfolded protein response. This in turn initiates apoptosis through the intrinsic pathway (mitochondrial) with subsequent recruitment of the extrinsic pathway (death receptor) to complete the process. The symmetry of the clinical and laboratory studies now permits the creation of rules for the future clinical application of ERT or phytoestrogen supplements: a five year gap is necessary after menopause to permit the selection of estrogen deprived breast cancer cell populations to become vulnerable to apoptotic cell death. Earlier treatment with estrogen around the menopause encourages ER positive tumor cell growth, as the cells are still dependent on estrogen to maintain replication within the expanding population. An awareness of the evidence that the molecular events associated with estrogen induced apoptosis can be orchestrated in the laboratory in estrogen deprived breast cancers, now support the clinical findings for the treatment of metastatic breast cancer following estrogen deprivation, decreases in mortality following long term antihormonal adjuvant therapy, and the results of ERT and ERT plus progestin in the Women’s Health Initiative for women over the age of 60. Principles have emerged to understand and apply physiologic estrogen therapy appropriately by targeting the correct patient populations.

48) Jordan, V. Craig, and Leslie G. Ford. “Paradoxical clinical effect of estrogen on breast cancer risk: a “new” biology of estrogen-induced apoptosis.” Cancer prevention research 4.5 (2011): 633-637.

Administration of estrogen replacement therapy (ERT) decreases the incidence of breast cancer, as shown in a double-blind, placebo-controlled randomized trial of the Women’s Health Initiative (WHI) in 10,739 postmenopausal women with a prior hysterectomy. Though paradoxical because estrogen is recognized to stimulate breast cancer growth, laboratory data support a mechanism of estrogen-induced apoptosis under the correct environmental circumstances. Long-term antiestrogen treatment or estrogen deprivation causes the eventual development and evolution of antihormone resistance. Cell populations emerge with a vulnerability, as estrogen is no longer a survival signal but is an apoptotic trigger. The antitumor effect of ERT in estrogen-deprived postmenopausal women is consistent with laboratory models.

49) Birrell, Stephen N., et al. “Disruption of androgen receptor signaling by synthetic progestins may increase risk of developing breast cancer.” The FASEB Journal 21.10 (2007): 2285-2293.

50)  de Lignieres, B., de Vathaire, F., Fournier, S., Urbinelli, R., Allaert, F., Le, M. G., and Kuttenn, F. Combined hormone replacement therapy and risk of breast cancer in a French cohort study of 3175 women. Climacteric. 5, (2002): 332–340

51) Fournier, A., Berrino, F., Riboli, E., Avenel, V., and Clavel-Chapelon, F. (2005) Breast cancer risk in relation to different types of hormone replacement therapy in the E3N-EPIC cohort. Int. J. Cancer. 114.3, (2005): 448–454

52) Writing Group for the Women’s Health Initiative Investigators. “Effects of conjugated equine estrogen in postmenopausal women with hysterectomy From the Women’s Health Initiative randomized controlled trial.” JAMA 29 (2004): 1701-1712.

53) Hulley, Stephen B., and Deborah Grady. “The WHI estrogen-alone trial—do things look any better?.” Jama 291.14 (2004): 1769-1771.

54) Writing Group for the Women’s Health Initiative Investigators, and Writing Group for the Women’s Health Initiative Investigators. “Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women’s Health Initiative randomized controlled trial.” Jama 288.3 (2002): 321-333.

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55) Lanari, Claudia, et al. “The MPA mouse breast cancer model: evidence for a role of progesterone receptors in breast cancer.” Endocrine-related cancer 16.2 (2009): 333.

56) Aldaz, C. Marcelo, et al. ” Medroxyprogesterone acetate accelerates the development and increases the incidence of mouse mammary tumors induced by dimethylbenzanthracene.” Carcinogenesis 17.9 (1996): 2069-2072.

57) Pazos, P., et al. “Mammary carcinogenesis induced by N-methyl-N-nitrosourea (MNU) and medroxyprogesterone acetate (MPA) in BALB/c mice.” Breast cancer research and treatment 20.2 (1992): 133-138.

58) Nagasawa, H., et al. “Medroxyprogesterone acetate enhances spontaneous mammary tumorigenesis and uterine adenomyosis in mice.” Breast cancer research and treatment 12.1 (1988): 59-66.

59) Horwitz, Kathryn B., and Carol A. Sartorius. “90 years of progesterone: progesterone and progesterone receptors in breast cancer: past, present, future.” Journal of Molecular Endocrinology 65.1 (2020): T49-T63.

In the early 2000s, the somewhat surprising finding that prolonged use of synthetic progestin-containing menopausal hormone therapies was associated with increased breast cancer incidence raised new questions about the role of PR in ‘tumorigenesis’.

First, we need to debunk the notion that progesterone ‘causes’ breast cancers. There is considerable experimental and clinical evidence that, alone and at physiological levels, progesterone is incapable of causing breast cancers so that its reputation as a ‘tumorigenic’ or ‘carcinogenic’ hormone is undeserved. It would be useful to have definitive proof of this once and for all and to eliminate use of these terms in reference to progesterone and the breast.

A 2019 meta-analysis by the Collaborative Group on Hormonal Factors in Breast Cancer confirmed the increased risk of breast cancer for MHT containing MPA, norethindrone acetate, or levonorgestrol, compared to never users or estrogen-only users (Collaborative Group on Hormonal Factors in Breast 2019). This was especially pronounced for long-term (>10 year) progestin users, who had twice the risk of developing breast cancer. Notably, this meta-analysis did not include bioidentical progesterone formulations, which had either no additional risk or even decreased breast cancer risk (discussed in Piette 2018).

Furthermore, it is important to distinguish between progestins and natural progesterone. Currently these tend to be lumped together leading to the view that progesterone is ‘carcinogenic’ (i.e. cancer causer). It is our opinion that natural progesterone does not ‘cause’ breast cancer but can expand it (see subsequent section). Hence, despite widespread linkage between the terms ‘progestins’ and ‘carcinogenesis’, we suggest that care must be taken with these ideas, as with the term ‘bioidentical’, until solid data are available, in women, differentiating between the natural hormone and any biosynthetic ones.

60) Bethea, Cynthia L. “MPA: Medroxy-Progesterone Acetate Contributes to Much Poor Advice for Women.” Endocrinology. (2011): 343-345.

61) Mal, Rahul, et al. “Estrogen receptor beta (ERβ): a ligand activated tumor suppressor.” Frontiers in Oncology 10 (2020): 587386.

62) Moyer, Dean L., et al. “Prevention of endometrial hyperplasia by progesterone during long-term estradiol replacement: influence of bleeding pattern and secretory changes.” Fertility and sterility 59.5 (1993): 992-997.

63) Fitzpatrick, Lorraine A., and Andrew Good. “Micronized progesterone: clinical indications and comparison with current treatments.” Fertility and sterility 72.3 (1999): 389-397.

64) Judd, Howard L., et al. “Effects of hormone replacement therapy on endometrial histology in postmenopausal women: the Postmenopausal Estrogen/Progestin Interventions (PEPI) Trial.” JAMA 275.5 (1996): 370-375.

65) Lieberman, Allan, and Luke Curtis. “In defense of progesterone: a review of the literature.” Alternative Therapies in Health & Medicine 23.7 (2017).

66) Thomson, Cynthia A., Emily Ho, and Meghan B. Strom. “Chemopreventive properties of 3, 3′-diindolylmethane in breast cancer: evidence from experimental and human studies.” Nutrition reviews 74.7 (2016): 432-443.

67) Reyes-Hernández, Octavio Daniel, et al. “3, 3′-Diindolylmethane and indole-3-carbinol: potential therapeutic molecules for cancer chemoprevention and treatment via regulating cellular signaling pathways.” Cancer Cell International 23.1 (2023): 180.

68) Williams, David E. “Indoles derived from glucobrassicin: Cancer chemoprevention by indole-3-carbinol and 3, 3′-diindolylmethane.” Frontiers in Nutrition 8 (2021): 734334.

69) Koli, Papita, et al. “Anticancer activity of 3, 3′‐diindolylmethane and the molecular mechanism involved in various cancer cell lines.” ChemistrySelect 5.37 (2020): 11540-11548.

70) Poloznikov, A. A., et al. “Antitumor Activity of Indole-3-carbinol in Breast Cancer Cells: Phenotype, Genetic Pattern, and DNA Methylation Inversion.” Applied Biochemistry and Microbiology 56.9 (2020): 909-919.

71) Zeng, Huawei, and Gerald F. Combs Jr. “Selenium as an anticancer nutrient: roles in cell proliferation and tumor cell invasion.” The Journal of nutritional biochemistry 19.1 (2008): 1-7.

72) Jackson, Matthew I., and Gerald F. Combs Jr. “Selenium as a cancer preventive agent.” Selenium: its molecular biology and role in human health. New York, NY: Springer New York, 2011. 313-323.

73) Reid, Mary E, et al. “The Nutritional Prevention of Cancer: 400 Mcg Per Day Selenium Treatment.” Nutrition & Cancer 60.2 (2008).

74) Ibrahim, Raihan Syah, and Aisyah Elliyanti. “The Potential of Iodine as A Treatment for Breast Cancer: A Narrative Review.” Jurnal Kesehatan Manarang 9.3 (2023): 159-165.

75) Glaser, Rebecca L., Anne E. York, and Constantine Dimitrakakis. “Incidence of invasive breast cancer in women treated with testosterone implants: a prospective 10-year cohort study.” BMC cancer 19 (2019): 1-10.

76) Ergul, Emel, et al. “Polymorphisms in the MTHFR gene are associated with breast cancer.” Tumor biology 24.6 (2004): 286-290.

77) Manyonda, Isaac, et al. “Could perimenopausal estrogen prevent breast cancer? Exploring the differential effects of estrogen-only versus combined hormone replacement therapy.” Journal of Clinical Medicine Research 14.1 (2022): 1-7.

78) Rajkumar, Lakshmanaswamy, et al. “Hormone-induced protection of mammary tumorigenesis in genetically engineered mouse models.” Breast Cancer Research 9 (2007): 1-11.

79) Bretthauer, Michael, et al. “Estimated lifetime gained with cancer screening tests: a meta-analysis of randomized clinical trials.” JAMA Internal Medicine 183.11 (2023): 1196-1203.

The findings of this meta-analysis suggest that current evidence does not substantiate the claim that common cancer screening tests save lives by
extending lifetime, except possibly for colorectal cancer screening with sigmoidoscopy.

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80) Shete, Nivida, Jordan Calabrese, and Debra A. Tonetti. “Revisiting Estrogen for the Treatment of Endocrine-Resistant Breast Cancer: Novel Therapeutic Approaches.” Cancers 15.14 (2023): 3647.

81) Chimento, Adele, et al. “Estrogen receptors-mediated apoptosis in hormone-dependent cancers.” International journal of molecular sciences 23.3 (2022): 1242.

82) Maximov, Philipp Y., et al. “Estrogen receptor complex to trigger or delay estrogen-induced apoptosis in long-term estrogen deprived breast cancer.” Frontiers in Endocrinology 13 (2022): 869562.

83) Abderrahman, Balkees, and V. Craig Jordan. “Estrogen for the treatment and prevention of breast cancer: a tale of 2 Karnofsky lectures.” The Cancer Journal 28.3 (2022): 163-168.

84) Jordan, V. Craig. “Molecular mechanism for breast cancer incidence in the Women’s Health Initiative.” Cancer Prevention Research 13.10 (2020): 807-816.

A sustained beneficial antibreast cancer action of estrogen alone noted in the WHI study is counter intuitive because the dogma is that estrogen, through the estrogen receptor (ER), is the primary signal for the initiation and growth of breast cancer.

However, the paradox (2), which is maintained throughout the WHI evaluation of more than 12 years, is estrogen causes a decrease in mortality and a decrease in the incidence of new breast cancers. This is counter intuitive to the scientific and medical community unless one embraces and understands the known clinical evidence that governs safe estrogen use for the treatment of breast cancer after menopause (3, 4). These were established 70 years ago.
An estrogen deprivation gap of 5 years after menopause is required for high-dose estrogen to be an effective treatment for breast cancer (Table 1; ref. 3). In addition, the same applies to 5 years of adjuvant tamoxifen therapy when recurrence and mortality continue to decrease after adjuvant tamoxifen treatment is stopped (5, 6).

Unexpectedly [WHI second Arm Premarin-Alone], a possible reduction of invasive breast cancer was noted: placebo 124 and estrogen 94, and this observation merited a follow-up analysis (9). The authors concluded that after a median of 11.8 years of follow-up and a median of 5.9 years of estrogen alone, there remained a lower incidence of breast cancer (placebo 199 cases and 151 estrogen cases).

A decade later, after discontinuing estrogen plus progestin, breast cancer incidence increased (HR, 1.29; 95% CI, 1.14–1.47; P < 0.001). These women had a 45% higher risk of dying from breast cancer (HR, 1.45; 95% CI, 0.98–2.015; P = 0.06). In addition, there was a 29% higher risk of dying after breast cancer diagnosis (HR, 1.29; 95% CI, 1.02–1.63; P = 0.03).

85) Yue, Wei, et al. “Pro-apoptotic effects of estetrol on long-term estrogen-deprived breast cancer cells and at low doses on hormone-sensitive cells.” Breast cancer: basic and clinical research 13 (2019): 1178223419844198.

86) Jordan, V. Craig. “The new biology of estrogen-induced apoptosis applied to treat and prevent breast cancer.” Endocrine-related cancer 22.1 (2015): R1-R31.

87) Jordan, V. Craig, and Leslie G. Ford. “Paradoxical clinical effect of estrogen on breast cancer risk: a “new” biology of estrogen-induced apoptosis.” Cancer prevention research 4.5 (2011): 633-637.

88) Song, Robert X-D., et al. “Effect of long-term estrogen deprivation on apoptotic responses of breast cancer cells to 17β-estradiol.” Journal of the National Cancer Institute 93.22 (2001): 1714-1723.

89) Sweeney, Elizabeth E., Ping Fan, and V. Craig Jordan. “Mechanisms underlying differential response to estrogen-induced apoptosis in long-term estrogen-deprived breast cancer cells.” International journal of oncology 44.5 (2014): 1529-1538.

90) Obiorah, Ifeyinwa E., Ping Fan, and V. Craig Jordan. “Breast cancer cell apoptosis with phytoestrogens is dependent on an estrogen-deprived state.” Cancer prevention research 7.9 (2014): 939-949.

91) Abderrahman, Balkees, and V. Craig Jordan. “Estrogen for the treatment and prevention of breast cancer: a tale of 2 Karnofsky lectures.” The Cancer Journal 28.3 (2022): 163-168.

The clinical description (8) and discovery of estrogen-induced apoptosis with further clinical application (7) in two Karnofsky lectures, separated by 38 years, has now provided a mechanistic insight into the adjuvant treatment of breast cancer (62), an insight into the “unexpected” results of the Women’s Health Initiative investigation of estrogen and estrogen/progestin given to women as hormone replacement at the age of 60 vs the Million Women Study of hormone replacement therapies in the general population. The results of the two epidemiological interventional studies were not comparable but instructive about mechanisms of hormone action in the real world if long-term estrogen deprivation occurs at menopause prior to HRT administration of estrogen alone produces a sustained decrease in breast cancer and the addition of medroxyprogesterone acetate not only reverses but increases breast carcinogenesis. Mechanisms are documents in the laboratory (42).

92) Estrogen Vindication, Part 1: Estrogen and the WHI (August/September 2020) Townsend Letter By Devaki Lindsey Berkson, DC

93) Estrogen Vindication, Part 2: Estrogen, Cancer Stem Cells, and Studies By Devaki Lindsey Berkson, DC

94) Cavalieri, Ercole, and Eleanor Rogan. “The 3, 4-quinones of estrone and estradiol are the initiators of cancer whereas resveratrol and N-acetylcysteine are the preventers.” International journal of molecular sciences 22.15 (2021): 8238.

Cancer can be initiated by increased formation of reactive estrogen metabolites called catechol estrogen-3,4-quinones. If estrogen metabolism becomes unbalanced and significant amounts of these quinones arise, depurinating estrogen-DNA adducts are primarily formed, leading to cancer-causing mutations

95) Almeida, Micaela, et al. “Influence of estrogenic metabolic pathway genes polymorphisms on postmenopausal breast cancer risk.” Pharmaceuticals 14.2 (2021): 94.

Genotype analysis of GSTM1 and GSTT1 null polymorphisms, CYP1B1 Val432Leu and MTHFR C677T polymorphisms was performed in 157 samples of women with hormone-dependent breast cancer and correlated with the age at diagnosis. The majority of patients with GSTT1 null genotype and with both GSTM1 and GSTT1 null genotypes were 50 years old or more at the diagnosis (p-value = 0.021 and 0.018, respectively). Older women with GSTM1 null genotype were also carriers of the CYP1B1Val allele (p-value = 0.012). As well, GSTT1 null and CYP1B1Val genotypes were correlated with diagnosis at later ages (p-value = 0.022). Similar results were found associating MTHFR C677T and GSTT1 null polymorphism (p-value = 0.034). Our results suggest that estrogen metabolic pathway polymorphisms constitute a factor to be considered simultaneously with models for breast cancer risk assessment.

96) Zahid, Muhammad, et al. “Resveratrol and N-acetylcysteine block the cancer-initiating step in MCF-10F cells.” Free Radical Biology and Medicine 50.1 (2011): 78-85.
Substantial evidence suggests that catechol estrogen-3,4-quinones react with DNA to form predominantly the depurinating adducts 4-hydroxyestrone (estradiol)-1-N3Ade [4-OHE1(E2)-1-N3Ade] and 4-OHE1(E2)-1-N7Gua. Apurinic sites resulting from these adducts generate critical mutations that can initiate cancer. The paradigm of cancer initiation is based on an imbalance in estrogen metabolism between activating pathways that lead to estrogen–DNA adducts and deactivating pathways that lead to estrogen metabolites and conjugates. This imbalance can be improved to minimize formation of adducts by using antioxidants, such as resveratrol (Resv) and N-acetylcysteine (NAcCys).

97) Yager, James D. “Mechanisms of estrogen carcinogenesis: The role of E2/E1–quinone metabolites suggests new approaches to preventive intervention–A review.” Steroids 99 (2015): 56-60.

Studies in hamsters, mice and rats have demonstrated that estradiol (E2), its interconvertible metabolite estrone (E1) and their catechol metabolites, in particular 4-hydroxy E2/E1, are carcinogenic in the kidney, uterus and mammary gland.
Various chemopreventive agents such as sulforaphane (SFN) and resveratrol have been shown in cell culture to block oxidative metabolism of E2/E1 and thus prevent DNA damage.

Increased levels of estrogen-quinone conjugates and DNA adducts have also been detected in urine of women at increased risk for and with breast cancer. These observations support the notion that targeting the estrogen/estrone metabolism pathway may be another way to reduce breast cancer risk.

98) Palliyaguru, Dushani L., et al. “Sulforaphane diminishes the formation of mammary tumors in rats exposed to 17β-estradiol.” Nutrients 12.8 (2020): 2282.

SFN-treated rats were protected significantly against mammary tumor formation compared to vehicle controls. Mammary glands of SFN-treated rats showed decreased DNA damage while serum free fatty acids and triglyceride species were 1.5 to 2-fold lower in SFN-treated rats.

99) Sung, Nam-Ji, and Sin-Aye Park. “Effect of Natural Compounds on Catechol Estrogen-Induced Carcinogenesis.” Biomedical Science Letters 25.1 (2019): 1-6.

The hydroxylation of estradiol results in the formation of catechol estrogens such as 2-hydroxyestradiol (2-OHE2) and 4-hydroxyestradiol (4-OHE2). These catechol estrogens are further oxidized to quinone metabolites by peroxidases or cytochrome P450 (CYP450) enzymes. Catechol estrogens contribute to hormone-induced carcinogenesis by generating DNA adducts or reactive oxygen species (ROS)….Here we focus specifically on the chemopreventive effects of these natural compounds against carcinogenesis induced by catechol estrogens.

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100) Arumugam, Arunkumar, Elaine A. Lissner, and Rajkumar Lakshmanaswamy. “The role of hormones and aromatase inhibitors on breast tumor growth and general health in a postmenopausal mouse model.” Reproductive Biology and Endocrinology 12 (2014): 1-13.

Ovariectomized nude mice were transplanted with MCF-7 breast cancer cells constitutively expressing aromatase. The mice were treated with different combinations and doses of steroids, [estrogen (25 pg, 40 pg, 100 pg), progesterone (6 ng) and testosterone (50 ng)] along with dehydroepiandrostenedione (100 ug). The mice were ovariectomized at 10 weeks of age. One week later, mice received transplants of MCF-7
cells stably transfected with the human aromatase gene. Each experimental group had 15 animals

However, current standard of practice considers hormones of any type absolutely contraindicated after hormone-receptor-positive breast cancer, with the assumption being that hormones “throw fuel on the fire” of cancer.  This assumption makes intuitive sense, since current treatment is to block remaining estrogens with aromatase
inhibitors, the exact opposite…Our results thus did not confirm the “throwing fuel on the fire” conception prevalent among clinicians.

In our experiments, we used steroids in their bioidentical form, as these hormones have been shown to possess a more positive risk-benefit profile than synthetic hormones which have been molecularly altered for patentability or oral bioavailability [27-30].

E plus P plus T treatment was associated with increased cognition, physical activity, and cardiovascular and bone health in the mouse model, and demonstrates the potential significance of hormone treatment in postmenopausal women.

In agreement with our study, testosterone therapy has also been shown to reduce breast cancer incidence in postmenopausal women and breast tumor growth in animal models [34-37].

Because estrogen-blocking aromatase inhibitors are the current adjuvant treatment after hormone-sensitive breast cancer, common sense would lead to the  ssumption that any treatment containing estrogen itself would lead to opposite, highly negative impact on tumor growth. However, this turned out not to be the case. As was the case for general health markers, maximal reduction in tumor growth was achieved by E plus P plus T treatment.

Furthermore, the antitumor effect of AI treatment, though notable when compared to control, did not excel when compared to hormone treatment. Treatment with AI had initial antitumor activity, consistent with the results of preclinical studies leading to the approval of AIs. However, three of five hormone treatment regimens provided similar suppression of tumor volume to the AI regimen. And with cessation of the AI treatment phase (chosen to be equivalent to the current clinical standard of care, 5 years), the antitumor effect of AIs diminished, leading to a steepened rise in tumor volume, while the most effective hormone regimens, including E plus P plus T, continued to more effectively suppress tumor volume.

Although an E plus P plus T regimen performed better in our study than AIs (the current standard of care) on measures of both tumor growth and general health, considerable momentum, as well as market forces, works against a reversal in treatment practice from hormone inhibitors to hormones. We therefore sought to determine whether addition of optimal hormones could improve quality of life and general health indicators when added to—instead of substituting for—AI treatment, without worsening tumor outcomes. Our results indicated the viability of this approach. When added to AIs, estradiol and progesterone significantly improved the general health of the animals as  measured by cardiac and bone health markers (although positive impact of hormones on cardiac and bone health markers was not as marked when added to AIs as when used alone), without promoting breast tumor growth. We discuss possible explanations for this seeming paradox—improved general health but lack of tumor stimulation—below.

Clinical studies have indicated that progesterone treatment helps maintain bone mass [75-77]. Progesterone supports bone formation by preventing glucocorticoid-induced bone loss [54]. Several animal and human studies have demonstrated progesterone’s positive effect on bone formation as well as inhibition of bone resorption [76-78]. Studies evaluating estrogen and progesterone supplementation suggest estrogen and progesterone have distinct but complementary roles in bone maintenance [75-77,79]. The addition of testosterone positively influences bone mass by preventing urinary calcium loss. Our findings demonstrate that the addition of hormones along with AI treatment is beneficial for bone health in postmenopausal women.

Conclusions: In summary, our results indicate that the use of appropriate
combinations of natural hormones along with, or instead of, classical breast cancer treatments is beneficial against postmenopausal symptoms and improves cardiac and osteoporotic health in the mouse model. The natural hormone combinations tested in this study provide evidence for a better alternative to standard aromatase inhibitor treatment following breast cancer in women.

101) Cold, Søren, et al. “Systemic or Vaginal Hormone Therapy After Early Breast Cancer: A Danish Observational Cohort Study.” JNCI Journal of the National Cancer Institute 114.10 (2022): 1347.

Among 8461 women who had not received VET [VAginal Estrogen Therapy] or MHT [Menopausal Hormone Therapy] before BC diagnosis, 1957 and 133 used VET and MHT, respectively, after diagnosis. Median follow-up was 9.8 years for recurrence and 15.2 years for mortality. The adjusted relative risk of recurrence was 1.08 (95% confidence interval [CI] = 0.89 to 1.32) for VET (1.39 [95% CI = 1.04 to 1.85 in the subgroup receiving adjuvant aromatase inhibitors]) and 1.05 (95% CI = 0.62 to 1.78) for MHT. The adjusted hazard ratios for overall mortality were 0.78 (95% CI = 0.71 to 0.87) and 0.94 (95% CI = 0.70 to 1.26) for VET and MHT, respectively.

In postmenopausal women treated for early-stage estrogen receptor–positive BC, neither VET nor MHT was associated with increased risk of recurrence or mortality. A subgroup analysis revealed an increased risk of recurrence, but not mortality, in patients receiving VET with adjuvant aromatase inhibitors.

 

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Estrogen Causes Breast Cancer
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102) Henderson, Brian E., R. K. Ross, and Leslie Bernstein. “Estrogens as a cause of human cancer: the Richard and Hinda Rosenthal Foundation award lecture.” Cancer research 48.2 (1988): 246-253.

103) Henderson, Brian E., R. K. Ross, and Leslie Bernstein. “Estrogens as a cause of human cancer: the Richard and Hinda Rosenthal Foundation award lecture.” Cancer research 48.2 (1988): 246-253.

https://joe.bioscientifica.com/downloadpdf/journals/joe/183/1/1830091.xml
194) Turan, V. K., et al. “The effects of steroidal estrogens in ACI rat mammary carcinogenesis: 17β-estradiol, 2-hydroxyestradiol, 4-hydroxyestradiol, 16α-hydroxyestradiol, and 4-hydroxyestrone.” Journal of endocrinology 183.1 (2004): 91-99.

105) https://jeffreydachmd.com/wp-content/uploads/2015/04/https://jeffreydachmd.com/wp-content/uploads/2015/04/Estrogen-carcinogenesis-in-breast-cancer-James-Yager-New-England-Journal-of-Medicine-2006.pdf-New-England-Journal-of-Medicine-2006.pdf
Yager, James D., and Nancy E. Davidson. “Estrogen carcinogenesis in breast cancer.” New England Journal of Medicine 354.3 (2006): 270-282.

conclusions

Studies of breast cancer have consistently found an increased risk associated with elevated blood levels of endogenous estrogen, clinical indicators of persistently elevated blood estrogen levels, and exposure to exogenous estrogen plus progestin through hormone-replacement therapy and the use of oral contraceptives. In experimental animals, estrogen treatment leads to the development of mammary tumors. Together, these observations support the hypothesis that estrogen is a mammary-gland carcinogen.
The mechanisms through which estrogens contribute to each phase of the carcinogenic process (initiation, promotion, and progression) are complex. The evidence suggests the participation of genotoxic estrogen metabolites and estrogen-receptor–mediated genomic and nongenomic signaling that affect cell proliferation and apoptosis in mammary tissue. The extent to which these two pathways
contribute to estrogen-mediated carcinogenesis and the ways by which genetic polymorphisms and environmental factors modify the effects of these pathways require further exploration. Even so, knowledge of the central role of estrogen in breast cancer has already led to the development of new preventive and therapeutic interventions that block receptor function or drastically reduce the levels of endogenous estrogen through the inhibition of its synthesis. The development of additional strategies on the basis of the inhibition of estrogen metabolism, inactivation of the reactive quinones, and specific inhibition of membrane estrogen-receptor– activated second-messenger pathways will probably lead to the availability of additional effective intervention approaches.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1832080/
106) Russo, J. I. H. R., and Irma H. Russo. “The role of estrogen in the initiation of breast cancer.” The Journal of steroid biochemistry and molecular biology 102.1-5 (2006): 89-96.

17-β-estradiol is able to induce complete neoplastic transformation of human breast epithelial cells, as proven by the formation of tumors in SCID mice. This model demonstrates a sequence of chromosomal changes that correlates with specific stages of neoplastic progression. The data also support the concept that 17-β-estradiol can act as a carcinogenic agent without the need of the ERα, although we cannot rule out thus far the possibility that other receptors such as ERβ, or other mechanisms could play a role in the transformation of human breast epithelial cells. These are areas of active research in our laboratory. The knowledge that breast cancer in women is associated with prolonged exposure to high levels of estrogens gives relevance to this model of estrogen induced carcinogenesis (6,8-10,15,16). For this reason this model is extremely valuable for furthering our understanding of estrogen induced carcinogenicity.

107) Liu, Chong, et al. “Advances in rodent models for breast cancer formation, progression, and therapeutic testing.” Frontiers in Oncology 11 (2021): 593337.

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108) Wood, Charles E., et al. “Comparative effects of oral conjugated equine estrogens and micronized 17β-estradiol on breast proliferation: a retrospective analysis.” Menopause 15.5 (2008): 978-983.

109) Levy, Barbara, and James A. Simon. “A Contemporary View of Menopausal Hormone Therapy.” Obstetrics & Gynecology 144.1 (2024): 12-23.

110) Bhavnani, Bhagu R., and Frank Z. Stanczyk. “Pharmacology of conjugated equine estrogens: efficacy, safety and mechanism of action.” The Journal of steroid biochemistry and molecular biology 142 (2014): 16-29.

111) Bhavnani, Bhagu R., Shui-Pang Tam, and XiaoFeng Lu. “Structure activity relationships and differential interactions and functional activity of various equine estrogens mediated via estrogen receptors (ERs) ERα and ERβ.” Endocrinology 149.10 (2008): 4857-4870.

112) Manjer, Jonas, Malte Sandsveden, and Signe Borgquist. “Serum Iodine and Breast Cancer Risk: A Prospective Nested Case–Control Study Stratified for Selenium Levels.” Cancer Epidemiology, Biomarkers & Prevention 29.7 (2020): 1335-1340.

Iodine has been suggested to protect against breast cancer, but there are no epidemiologic studies on individual risk. An interesting finding is that in areas where the exposure to both selenium and iodine are high (e.g., Japan), the risk of breast cancer is lower than in areas where selenium is high and iodine low (e.g., United States), or in areas where both are low (e.g., Northern Europe). The aim of this study was to investigate the association between prediagnostic serum iodine levels and subsequent breast cancer risk, and to investigate if this potential association was modified by selenium levels.

Methods: The Malmö Diet and Cancer Study provided prediagnostic serum samples and the current analysis included 1,159 breast cancer cases and 1,136 controls. Levels of baseline serum iodine and selenium were analyzed. A logistic regression analysis yielded ORs with 95% confidence intervals adjusted for potential confounders.

Results: There was no evidence of an overall association between iodine levels and risk of breast cancer. Among women with high selenium levels (above the median), high iodine levels were associated with a lower risk of breast cancer; the OR for above versus below the median was 0.75 (0.57-0.99). The corresponding OR for women with low selenium was 1.15 (0.87-1.50), and the P interaction was 0.06.

Conclusions: The combination of high serum iodine levels and high selenium levels was associated with a lower risk of breast cancer.

113) Flores, Valerie A., and Hugh S. Taylor. “The effect of menopausal hormone therapies on breast cancer: avoiding the risk.” Endocrinology and Metabolism Clinics 44.3 (2015): 587-602.

Further support for progestogens’ role in breast cancer comes from studies analyzing progestogen effects on estrogen metabolizing enzymes in breast cancer cells. Using T47-D and MCF-7 cells, Xu et al demonstrated that E2+MPA increased the expression of estrogen activating enzymes—aromatase, 17 beta hydroxysteroid dehydrogenase type 1 (17BHSD1), and sulfatase, but did not increase expression of the estrogen inactivating enzymes, 17 beta hydroxysteroid dehydrogenase type 2 and sulfotransferase.25 The increase in cellular expression of estrogen activating enzymes with E2+MPA was greater than that seen when cells were treated with E2 alone. Interestingly, the increase in estrogen activating enzymes was not associated with an increase in cell proliferation, although there was an increase in estrogen levels. It is known however that locally increased estrogen levels are seen in the breast cancer cell environment, and this high-estrogen environment facilitates cancer cell growth.25 Thus, it is postulated that MPA may exert its carcinogenic effect via induction of a local hyperestrogenic state, rather than directly through cell proliferation.

Dr Wood Monkey studies;
A randomized trial in adult ovariectomized female macaques was used to study the effects of progestogens on risk markers for breast cancer.36 This primate model is ideal for studying hormonal effects on breast tissue, as they have over a 90% average genetic coding sequence identity to humans.37,38 In addition, the steroid receptor response to sex hormone administration, and the development of neoplastic breast tissue in this model is similar to what occurs in humans.36 The postmenopausal animals received one of four treatment regimens, with doses reflecting commonly prescribed doses in MHT for postmenopausal women—placebo, E2 daily, E2+P4 daily, or E2+MPA daily. After two months of treatment macaques treated with E2+MPA demonstrated a significant increase in proliferation of breast lobular and ductal cells, compared to placebo; this proliferative activity was not seen with E2+P4 treatment.36 There was also increased expression of proliferation markers Ki67 and cyclin B1 in the E2+MPA treated monkeys, but not in the E2+P4 treatment group. In a follow-up study using this same animal model, Wood et al also demonstrated differences in gene expression profiles for a given progestogen treatment.15 Breast biopsies were collected after two months of treatment, and analyzed for differences in gene expression. It was found that breast tissue exposed to E2+MPA demonstrated increased expression of genes in the ErbB proliferative pathway—epidermal growth factor (EGF) and transforming growth factor alpha (TGFa). Genes of the Jak/Stat signal transduction pathway, including c-MYC gene expression were also differentially expressed, with a 2.5 fold change in the E2+MPA treatment when compared to control (P< 0.01). cMYC induces signals for cell proliferation, and is known to be involved in tumorigenesis.15 There were no significant effects on genes related to apoptosis (TGF beta pathway), or genes related to estrogen receptor activity (Trefoil 1, stanniocalcin, cyclin D) seen in any group of treated animals. Thus, rather than directly enhancing ER’s mediated response to increase breast cell proliferation, MPA may instead act via modulation of growth factor pathways. E2+MPA enhanced E2’s effect on ErbB pathway related genes, providing further support for MPA’s role in promoting breast cell proliferation through growth factor signaling mechanisms.15

CEE and B-ring Steroids”’

The choice of CEE in the ET arm of the WHI may explain the favorable effects seen on the breast. CEE contains a mixture of multiple estrogens, and each estrogen-type not only preferentially binds the two estrogen receptors, but may also exert differential actions depending on the target tissue.55,56 While E2 is the well characterized estrogen, less is known about the many estrogenic components of CEE. 56 Unlike E2, these other estrogens differ in their B-ring saturation and in their chemical moieties at the 17-position. 55 In a study assessing the activity of an estrogenic compound with similarities to several estrogens in CEE (NCI 122— 17 beta-methyl-17alpha-dihydroequilenin), it was found that NCI 122, as well as two other equine estrogens, were estrogen agonists that binds both ER alpha and beta, but are less potent estrogens than E2.55 Despite their lower potency, NCI 122 and equine estrogens are able to exert transcriptional changes distinct from E2, which are postulated to account for the positive effects seen in several tissue types. 57–60 57–60

Bhavnani et al analyzed the effects of 11 equine estrogens (in CEE preparations) on the transcriptional activity of ER alpha and beta, and found that many of the equine estrogens preferentially bind ER beta.61 ER beta activation can inhibit ER alpha activity on cell proliferation. 62,63 This inhibition induced by equine estrogens may in part explain the decreased risk of breast cancer observed in the WHI ET study. Further support for beneficial SERM (selective estrogen receptor modulatory)-like properties of CEE comes from work by Sang et al, where the effects of CEE and E2 on breast cancer cells were compared.64 CEE and E2 were noted to have distinct effects on gene expression. Research by Berrodin et al also demonstrated that several estrogenic compounds in CEE act as partial estrogen agonists; 65 thus, like SERMs, the differences in binding and downstream cell signaling may afford CEE with specific tissue manifestations that are unlike estradiol’s purely stimulatory effects.64 Additional research identifying which equine estrogens exert more SERM-like properties is needed, as they can not only be preferentially used in menopausal hormone therapy (MHT), but perhaps may even be of benefit in the treatment of breast cancer.

114) Ochnik, Aleksandra M., et al. “Antiandrogenic actions of medroxyprogesterone acetate on epithelial cells within normal human breast tissues cultured ex vivo.” Menopause 21.1 (2014): 79-88.

115) Mohammed, Hisham, et al. “Progesterone receptor modulates ERα action in breast cancer.” Nature 523.7560 (2015): 313-317.

We conclude that activation of PR results in a robust association between PR and the ERα complex.

Progesterone blocks ERα+ tumour growth…PR is a critical determinant of ERα function due to crosstalk between PR and ERα. In this scenario, under estrogenic conditions, an activated PR functions as a proliferative brake in ERα+ breast tumours by re-directing ERα chromatin binding and altering the expression of target genes that induce a switch from a proliferative to a more differentiated state 6.

Also see (61) duplicate

116) Mal, Rahul, et al. “Estrogen receptor beta (ERβ): a ligand activated tumor suppressor.” Frontiers in oncology 10 (2020): 587386.

NATURAL ERβ LIGANDS – High ERβ1 expression is associated with improved overall survival in women with breast cancer. The promise of ERβ activation, as a potential targeted therapy, is based on concurrent activation of multiple tumor suppressor pathways with few side effects compared to chemotherapy. Thus, ERβ is a nuclear receptor with broad-spectrum tumor suppressor activity, which could serve as a potential treatment target in a variety of human cancers including breast cancer. Further development of highly selective agonists that lack ERα agonist activity, will be necessary to fully harness the potential of ERβ… As with ERα, estrogenic compounds including estradiol, estrone,
and estriol activate ERβ. Relative to ERα, ERβ binds estriol and ring B unsaturated estrogens with higher affinity, while the reverse is true of 17β-estradiol and estrone (7–10). On the other
hand, the dihydrotestosterone metabolites 5-androstenediol and 3β androstanediol are relatively selective (3-fold) for ERβ over ERα (11).

117) Perkins MS, Louw-du Toit R, Africander D. A comparative characterization of estrogens used in hormone therapy via estrogen receptor (ER)-alpha and -beta. J Steroid Biochem Mol Biol. (2017) 174:27–39.

118) Bhavnani BR, Tam SP, Lu X. Structure activity relationships and differential interactions and functional activity of various equine estrogens mediated via estrogen receptors (ERs) ERα and ERβ. Endocrinology. (2008) 149:4857–70.

119) Barkhem T, Carlsson B, Nilsson Y, Enmark E, Gustafsson J, Nilsson S. Differential response of estrogen receptor alpha and estrogen receptor beta to partial estrogen agonists/antagonists. Mol Pharmacol. (1998) 54:105–12.

120) Katzenellenbogen BS. Biology and receptor interactions of estriol and estriol derivatives in vitro and in vivo. J Steroid Biochem. (1984) 20:1033–7.

121) Paterni I, Granchi C, Katzenellenbogen JA, Minutolo F. Estrogen receptors alpha (ERα) and beta (ERβ): subtype-selective ligands and clinical potential. Steroids. (2014) 90:13–29.

122) Glaser, Rebecca L., Anne E. York, and Constantine Dimitrakakis. “Incidence of invasive breast cancer in women treated with testosterone implants: a prospective 10-year cohort study.” BMC cancer 19 (2019): 1-10.

123) L’hermite M, Simoncini T, Fuller S, Genazzani AR. Could transdermal estradiol + progesterone be a safer postmenopausal HRT? A review. Maturitas. 2008 Jul-Aug;60(3-4):185-201. Hermite_Could_Transdermal_estradiol_Progesterone_be_Safer_HRT

124) Fournier, A., Berrino, F., & Clavel-Chapelon, F. (2008). Unequal risks for breast cancer associated with different hormone replacement therapies: results from the E3N cohort study. Breast Cancer Res Tr, 107(1), 103-111.
Unequal_Risks_Breast_Cancer_hormone_replacement_E3N_French_cohort_study_Fournier_2008

125) Fournier, A., Fabre, A., Mesrine, S., Boutron-Ruault, M.-C., Berrino, F., & Clavel-Chapelon, F. (2008). Use of different postmenopausal hormone therapies and risk of histology- and hormone receptor-defined invasive breast cancer. J Clin Oncol, 26(8), 1260-1268. Use of Different Postmenopausal Hormone Therapies and Risk Invasive Breast Cancer Fournier Agnès J Clin Oncology 2008

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