Don’t Monkey With My Hormones

Formosan macaque Dont Monkey With My Hormones Bioidentical

Don’t Monkey With My Hormones!

by Jeffrey Dach MD

This article is part two of a series. For Part One Click Here

Hormone Monkey Studies

Hormone Studies from the Primate Center at Winston-Salem are quite revealing and allow us to answer questions about different effects of various hormone formulations.

Header image: Formosan macaque monkey, Endemic animals of Taiwan.Photo by KaurJmeb, in Taipei Zoo, 2005/04/23 courtesy of wikimedia commons.

If you are an avid reader of these pages, then you know I often quote the 2008 French Cohort Study by Fournier demonstrating safety of bioidentical hormones.  This study showed that bioidentical hormone users in France (using Estradiol and Progesterone) had same breast cancer risk as non-hormone users.  In other words, there was no increased risk of breast cancer with this combination of bioidentical hormones. (1)

Here is the  Data from Table 3 from the French Cohort study (Fournier 2008):

Hormone Combination             Relative Risk of Invasive Breast Cancer (1)

Non-User                                                              1.0
Estrogen (Estradiol) alone                                      1.29  (p=0.73 non-significant)
Estrogen (estradiol) / Progesterone (Bioidentical)    1.0
Estrogen (Estradiol) / Medroxyprogesterone            1.48

Adding MedroxyProgesterone (MPA)

When the added progestin is  Medroxyprogesterone (MPA), there is increased breast cancer risk (RR=1.48).  However, there is no increased risk with the addition of progesterone (RR=1.0).  Confirmatory findings were seen in the WHI study (First Arm) which also showed increased invasive breast cancer with the combination of Premarin and Medroxyprogesterone (MPA) also called Prempro.

Estrogen Alone

Now that we have the 11 year follow-up data of the Second Arm, Premarin-Alone (CEE horse estrogen) study of the Women’s Health Initiative, we can ask some more questions.  The Premarin-Alone Arm showed a 20-27% decrease in breast cancer  compared to placebo.

Why Less Cancer with Premarin-Alone, and More with Estradiol Alone ?

One might ask the obvious question, “Why is Premarin-Alone associated with decreased breast cancer risk compared to non-hormone users, while Estradiol-alone (bioidentical) is associate with a 29% increase in invasive breast cancer in the French Cohort study (p=0.73 non-significant)?

Monkey Studies Explain the Findings

The answer comes from Dr Wood at the the primate center in Winston Salem in a 2008 report using Macaque monkeys.  Dr. Wood compared Premarin to estradiol as hormone replacement in a primate model, and found a highly significant 259-330% increase in breast cell proliferation in estradiol treated monkeys compared to controls.  The Premarin (CEE) treated monkeys however, had far less cell proliferation, only 75% was noted using the KI-67 antigen test of cell proliferation. (2)

This difference in cell proliferation, indicates a stonger estrogenic effect with estradiol compared to Premarin. This explains why estradiol alone, used in the French Cohort study, is associated with increased breast cancer risk, while Premarin-alone, used in the WHI second arm, is not associated with increased risk for breast cancer. This second arm of the WHI actually showed 23% less breast cancer in the Premarin-alone users.

How to Make the Estradiol Less Proliferative?

The question is, how can we make menopausal hormone replacement safer? How can we make the estradiol less proliferative on breast tissue?  This brings us to the importance of adding progesterone to an estradiol-alone HRT regimen. For example, commercially available estradiol patches such as Vivelle-Dot and Climara Patch contain estradiol-alone.  For women with surgically induced menopause after hysterectomy, the mainstream medical system will routinely given an estrogen-alone regimen. These women have undergone hysterectomy and have no uterus, so a progestin is not needed for endometrial protection. However, some menopasual women on estradiol-alone may be at increased risk of breast cancer. Reducing breast cell proliferatio is the key. This can be done by combining micronized natural progesterone to the estradiol. It can also be done by altogether switching from estradiol-alone to the Bi-est/progesterone combination.  We preferentially use a Bi-est/ progesterone combination cream to make sure both hormones are taken together in the proper ratio to prevent endometrial hyperplasia and reduce breast proliferation. In addition, every post-menopausal woman will take oral micronized progesterone capsule (100-200 mg) nightly. Micronized progesterone is FDA approved (1988, Solvay) for prevention of endometrial hyperplasia caused by estradiol, thus preventing endometrial cancer.

Breast Cancer Prevention Program

Our breast cancer prevention program includes: An HRT formula optimized to include Bi-est, and both topical and oral progesterone. For further breast cancer prevention, we add: Iodine testing and supplementation when found low. Testosterone topical cream. DIM (Di-Indole-Methane), Methyl-folate to cover those patients harboring a MTHFR mutation, Vitamin D3, and Selenium when testing reveals low levels.

Typical Compounded Dosing Schedules

In 2011, Dr. Andres D Ruiz provided typical Menopausal HRT Dosing Schedules in Table 1 of her publication. (28)

Why is Bi-Est Superior to Estradiol Alone ?

Bi-Est is a combination of estradiol (E2) with estriol (E3), in a ratio of 20% estradiol, and 80% estriol. Studies show that estriol is associated with less breast proliferation, and is thought to be breast cancer preventive. Estriol’s protective effects are found to be preferential activation of estrogen receptor Beta (ER-Beta) which is breast cancer suppressive. (7-13)

How Does Estriol (E3) Prevent Breast Cancer ?

Estriol and the Estrogen Receptor Beta.

As it turns out, basic science has given us important answers here.  There are actually two estrogen receptors, ER- Alpha, and ER-Beta.  ER- Alpha is associated with breast cell proliferation, while ER-Beta with suppression of proliferation and prevention of breast cancer.  Estradiol (E2) binds equally to both receptors, whereas Estriol (E3) binds preferentially to ER-Beta, explaining its protective effect.

Testosterone also has breast cancer protective effects because its metabolites bind preferentially to ER-Beta. Synthetic progestins have androgenic effects which disrupt the beneficial ER-Beta cancer suppressive effects of testosterone, thus explaining carcinogenicity of synthetic progestins. (21-26)

Bi-Est is Safer then Estradiol Alone

Armed with this information about estriol (E3), we can now be confident the Bi-Est combination (containing 20% estradiol/ 80% estriol), combined with progesterone and testosterone, is the safest HRT regimen currently available. However, we want even more breast cancer protection with the addition of Iodine (Iodoral), DIM (Di-Indole-Methane), Methy-folate, Vitamin D, and selenium supplementation.

Protective Effects of Progesterone Compared with Harmful Effects of Medroxyprogesterone – Breast Cell Proliferation

Let us now take a moment look at a few primate studies comparing the efficacy and adverse effects of natural progesterone to its synthetic progestin counterpart, medroxyprogesterone (MPA). How can we explain why the synthetic progestins such as medroxyprogesterone (MPA) cause increased breast cancer risk while natural bioidentical progesterone is breast cancer protective?

In 2007, Dr. Charles E. Wood was interested in how to attenuate breast cell proliferation induced by estradiol in a primate model. Dr. Wood compared the effect of medroxyprogesterone (MPA) to that of progesterone in a primate model of hormone replacement. The estradiol/MPA combination increased breast cell proliferation, while the estradiol/progesterone combination did not. Dr Wood writes:

Estradiol plus medroxyprogesterone (MPA) significantly increased breast cell proliferation using Ki67 markers. However, estradiol with progesterone did not increase cellular proliferation... These findings suggest that oral micronized progesterone has a more favorable effect on risk biomarkers for postmenopausal breast cancer than medroxyprogesterone acetate. (3) Note: the Ki-67 marker is routinely used as a measure of breast cell proliferation.

Previous primate studies by Dr. Cline in 1998 showed the same increased breast cell proliferation with addition of medroxyprogesterone (MPA) to Premarin treated monkeys. In 1998, Dr Cline concluded:

These findings indicate that progestogens (MPA) may exacerbate, not antagonize mammary gland proliferation induced by estrogen (Premarin) replacement therapy. (5)

Protective Effect of Progesterone in Human Studies

The protective effect of natural bioidentical progesterone was confirmed in two placebo controlled randomized double blind human trials by Drs. King-Jen Chang(1995) and Jean-Michel Foidart (1998). Dr. Chang studied 40 post-menopausal women planning breast lumpectomy. A topical gel containing either placebo, estradiol (E2), natural progestrone (P), or combination of E2/P, was applied topically to the breast daily for two weeks preceding lumpectomy. King-Jen Chang found the application of topical progesterone (P) gel to the breast reduced the estradiol (E2)-induced proliferation of normal breast epithelial cells in these women.(19)

Dr. Foidart (1998) studied forty untreated postmenopausal women who were planning aesthetic breast surgery. Natural progesterone applied to the breast as a topical gel for 14 days prior to aesthetic breast surgery, or excision of a benign lesion. Dr. Foidart found the progesterone topical gel reduced the proliferative effects of estrogen, thereby explaining its cancer preventive effect. Breast epithelial cell proliferation is the underlying factor for increasing cancer risk. When proliferation is increased, this increases risk for breast cancer. When proliferation is suppressed or decreaed, then this decreases risk for breast cancer. (20)

In 2011, Dr. Andres D Ruiz studies the effectiveness of natural (bioidentical) hormone replacement in menopausal women in a cohort study writing:

Two RCTs [randomized controlled trials] by Chang and colleagues [21] and Foidart and colleagues [22] demonstrated that women receiving topical P4 [natural progesterone] experienced a reduction in breast epithelial proliferative markers via reductions in mitotic divisions and proliferating cell nuclear antigen (PCNA) labeling index % compared to placebo. These studies support the belief that P4 [natural progesterone] may prevent breast epithelial hyperplasia.(28)

Progesterone Health Benefits vs. MPA Adverse Heath Effects

Health benefits of progesterone extend to cardiovascular system, brain and neurologic system. In 2011, Dr. Cynthia L Bethea studied the effects of hormone replacement on mood, finding improved mood with the estradiol/progesterone combination is reversed by the estradiol/ synthetic progestin (MPA) combination. In fact, all the benefical health outcomes seen with progesterone on brain, breast, and cardiovascular system are reversed by synthetic progestin, MPA, writing:

The actions of the natural hormones are significantly different from those of Premarin and MPA…progesterone has potent neuroprotective effects and MPA does not…We found that in nonhuman primates, estradiol or equine estrogens increase the expression of tryptophan hydroxylase (TPH), the rate-limiting enzyme in serotonin synthesis…In contrast, supplementation with MPA completely blocked the effect of equine estrogens. Thus, MPA endangers brain cells and potentially facilitates stress and depression…MPA reduces the dilatory effect of estrogens on coronary arteries, increases the progression of coronary artery atherosclerosis, accelerates low-density lipoprotein uptake in plaque, increases the thrombogenic potential of atherosclerotic plaques, and promotes insulin resistance and its consequent hyperglycemia in primates, whereas progesterone does not…Most of the research papers showing significantly better outcomes in brain, breast, and cardiovascular parameters with estradiol plus progesterone instead of MPA end with rational statements to the effect that hopefully the data will lead to better hormone therapy. (15)

The Protective Effect of  Testosterone in Rhesus Monkey Studies

In 2000, Dr. Jian Zhou studied ovarectimized rhesus monkeys, rendered estrogen, progesterone and testosterone deficient. Following this, the rhesus monkeys were treated with placebo, 17β estradiol (E2) alone or in combination with progesterone (E2/P) or in combination with testosterone (E2/T), or tamoxifen for 3 days. Dr. Jian Zhou found estradiol alone increased breast epithelial cell proliferation as expected. However, co-administration of testosterone with the estradiol reduced breast epithelial cell proliferation by 40 percent indicating breast cancer protective effects. Remember ER-alpha is the cancer inducer receptor, while ER-Beta is the cancer suppressor receptor. The co-administration of testosterone completely abolished the estradiol (E2) induced ER-alpha expression. Dr Jian Zhou writes:

Progesterone did not alter E2’s proliferative effects, but testosterone reduced E2-induced proliferation by —40% (P< 0.002) and entirely abolished E2-induced augmentation of ERα expression…These observations showing androgen-induced down-regulation of mammary epithelial proliferation and ER expression suggest that combined estrogen/androgen hormone replacement therapy might reduce the risk of breast cancer associated with estrogen replacement. (26-27)

Twenty four years ago, Dr. Jian Zhou made the startling discovery that the estrogen/testosterone combination is the optimal way to administer menopausal hormone replacement. For this reason, all postmenopausal hormone replacement programs should include testosterone.  For more on this see the article on Testosterone for prevention and treatment of breast cancer.

Conclusion: Studies of hormone treated monkeys are illuminating, showing synthetic progestins such as MPA are carcinogenic and should be avoided. On the other hand, progesterone and testosterone are breast cancer protective when used in combination with estradiol, as both reduce breast epithelial cell proliferation induced by estradiol. This was confirmed in two human RCT’s (randomized controlled trials). Estriol, also called E3, is breast cancer protective, preferentially binding and activating ER-Beta. This makes it obvious the optimal menopausal hormone replacement program should include Bi-est (estradiol/estriol), Progesterone, and Testosterone.

Our routine starting formula is a topical cream containing:
5 mg/gram Bi-est (20% estradiol / 80% estriol)
50 mg/gram progesterone.
Half gram of cream is applied topically twice a day providing one gram of cream daily.

A separate topical cream containing:
Testosterone 12 mg per gram
Quarter gram of cream is applied topically daily (3 mg testosterone)
The actual dosages are titrated up or down depending on patients’ response to treatment, so that final dosage may differ from starting dosage in most cases. (Note: For post-menopausal women, progesterone is commonly added to the testosterone cream. However for young cycling women, DHEA is combined rather than the progesterone, usually taken on a 12-26 day monthly schedule for young cycling women to avoid interference with ovulation.)

This has been part two of a series. For Part One click here:

Articles with related interest:

Errors in Modern Medicine: Fear of Estrogen

The Health Benefits of Menopausal Hormone Replacement

Estrogen for Prevention and Treatment of Osteoporosis

The Safety of Bio-Identical Hormones

The Importance of BioIdentical Hormones

Bioidentical Hormones Prevent Arthritis

Bioidentical Hormone Estrogen Prevents Heart Disease

Morning Rounds With Steven Economou MD

Waking Up from the Synthetic Hormone Nightmare

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

Links and References :

1) Fournier, Agnès, et al. “Use of different postmenopausal hormone therapies and risk of histology-and hormone receptor-defined invasive breast cancer.” Journal of clinical oncology: official journal of the American Society of Clinical OncologyJournal of clinical oncology: official journal of the American Society of Clinical Oncology 26.8 (2008): 1260.

In the present analysis, the use of estrogen+progesterone was not significantly associated with the risk of any breast cancer subtype, though we found trends of increasing risks with increasing duration of use for lobular and ER+/PR− carcinomas. … Use of estrogen+other progestagens was associated with increases in risk of both ductal and lobular carcinomas, and of ER+/PR+ and ER+/PR− carcinomas.

However, in vivo, progesterone has been found to oppose the proliferative effects of estradiol on breast tissue of pre- and postmenopausal women.50,51 The contrary has been found for medroxyprogesterone acetate (MPA) in postmenopausal women52 or surgically postmenopausal macaques.53

In such a study on macaques, compared to placebo, estradiol+MPA resulted in significantly greater proliferation in lobular and ductal breast epithelium, while estradiol+micronized progesterone did not. 54 These studies support our findings suggesting that, when combined with an estrogen, progesterone may have a safer risk profile in the breast than some other progestagens.

2008  Dr Wood: Estradiol Compared to Premarin –  standard doses of CEE may result in less  estrogen-induced epithelial proliferation in the breast compared with E2.

2) 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.

To evaluate the effects of oral conjugated equine estrogens (CEE) and micronized 17beta-estradiol (E2) on breast proliferation in a postmenopausal primate model.
DESIGN: Data from nine studies were analyzed retrospectively. The primary outcome measure was breast epithelial proliferation determined by immunolabeling for the Ki67 antigen. Other measures included progesterone receptor expression and endometrial thickness (as surrogate markers of systemic estrogen exposure) and urinary estrogen metabolite profile. All CEE doses were given at the human equivalent of 0.625 mg/day (n = 281), whereas E2 was given at the human equivalent of 1.0 mg/day or less (n = 131).
RESULTS: Oral CEE (Premarin) resulted in a modest overall increase in breast epithelial proliferation of 75% that reached significance at P < 0.05 compared with placebo in one of four parallel-arm studies.

In contrast, oral E2(estradiol) resulted in a more substantial increase in breast epithelial proliferation of 259% (all studies) to 330% (parallel-arm studies only) that reached significance at P < 0.05 in all five E2 studies evaluated. Breast epithelial expression of progesterone receptor, a widely used marker of estrogen receptor activity, and endometrial thickness showed similar increases after treatment with CEE and E2 (P < 0.05 in all available studies). Relative amounts of urinary methoxyestrogens and the 2-hydroxyestrogen-to-16 alpha-hydroxyestrone ratio were higher after CEE compared with E2 treatment (P < 0.05 for all).
CONCLUSIONS: This retrospective analysis of oral estrogen effects in postmenopausal macaques suggests that standard doses of CEE may result in less estrogen-induced epithelial proliferation in the breast compared with E2.

2007 Dr. Wood – Estradiol plus either Progesterone or Medroxyprogesterone.  Increased breast proliferation with E2 plus MPA, but no increased proliferation with E2 and Progesterone

3) Wood, Charles E., et al. “Effects of estradiol with micronized progesterone or medroxyprogesterone acetate on risk markers for breast cancer in postmenopausal monkeys.Breast cancer research and treatment 101 (2007): 125-134.

The addition of the synthetic progestin medroxyprogesterone acetate (MPA) to postmenopausal estrogen therapy significantly increases breast cancer risk. Whether this adverse effect is specific to MPA or characteristic of all progestogens is not known. The goal of this study was to compare the effects of oral estradiol (E2) given with either MPA or micronized progesterone (P4) on risk biomarkers for breast cancer in a postmenopausal primate model. For this randomized crossover trial, twenty-six ovariectomized adult female cynomolgus macaques were divided into social groups and rotated randomly through the following treatments (expressed as equivalent doses for women):

(1) placebo;
(2) E2 (estradiol)(1 mg/day);
(3) E2 + P4 (progesterone)(200 mg/day); and
(4) E2 + MPA (medroxyprogesterone)(2.5 mg/day).

Hormones were administered orally, and all animals were individually dosed. Treatments lasted two months and were separated by a one-month washout period. The main outcome measure was breast epithelial proliferation, as measured by Ki67 expression.

Compared to placebo, E2 + MPA resulted in significantly greater breast proliferation in lobular (P < 0.01) and ductal (P < 0.01) epithelium, while E2 + P4 did not. Intramammary gene expression of the proliferation markers Ki67 and cyclin B1 was also higher after treatment with E2 + MPA (P < 0.01) but not E2 + P4. Both progestogens significantly attenuated E2 effects on body weight, endometrium, and the TFF1 marker of estrogen receptor activity in the breast. These findings suggest that oral micronized progesterone has a more favorable effect on risk biomarkers for postmenopausal breast cancer than medroxyprogesterone acetate.

2005 Overview of Monkey Studies – prevention of premature CAD

4) Clarkson, Thomas B., and Susan E. Appt. “Controversies about HRT—lessons from monkey models.” Maturitas 51.1 (2005): 64-74.

Lessons from monkey models contribute significantly to a better understanding of the controversies in reconciling the differences in postmenopausal hormone treatment outcomes between observational and randomized trial data. Monkey studies brought attention to premenopausal estrogen deficiency with resulting premature coronary artery atherosclerosis.

Recently, those monkey studies were confirmed for premenopausal women in the NHLBI-sponsored Women’s Ischemia Syndrome Evaluation (WISE) Study. Monkey studies have provided convincing evidence for the primary prevention of coronary artery atherosclerosis when estrogens are administered soon after the development of estrogen deficiency. Equally convincing are the data from monkey studies indicating the total loss of these estrogens beneficial effects if treatment is delayed for a period equal to six postmenopausal years for women.

An attempt has been made using the monkey model to identify the hormone treatment regimen most effective in preventing the progression of coronary artery atherosclerosis. By a substantial margin, the most effective approach is that of using estrogen containing oral contraceptive during the perimenopausal transition, followed directly by hormone replacement therapy postmenopausally. Because of similarities between human and nonhuman breast, monkeys have had a major role in clarifying controversies surrounding the breast cancer risk of estrogen only versus estrogen plus progestin therapies. The results of monkey studies suggest little or no effects of estrogen (Premarin) only treatment; whereas, estrogen (Premarin)+progestin clearly increases breast cancer risk.

1998 Dr Cline – Macaques Monkeys- Breast proliferation increased by addition of MPA to Premarin.

5) Cline, J. Mark, et al. “Effects of conjugated estrogens, medroxyprogesterone acetate, and tamoxifen on the mammary glands of macaques.” Breast cancer research and treatment 48 (1998): 221-229.

The purpose of this work was to examine the mammary glands of adult, ovariectomized female cynomolgus macaques (Macaca fascicularis) in a long-term study of the effects of hormone treatments on chronic disease.

Treatments included conjugated equine estrogens (CEE), medroxyprogesterone acetate (MPA), CEE+MPA, and tamoxifen. Doses were scaled from those given women. Treatments were given in the diet for three years, followed by necropsy and tissue collection. Endpoints evaluated included glandular histology, histomorphometry, and immunohistochemical detection of the proliferation marker Ki-67, estrogen receptor (ER), and progesterone receptor (PR) in mammary epithelial cells.

Major findings were as follows: CEE (Premarin) induced PR expression and focal to diffuse lobuloalveolar proliferation.

Proliferation was increased by the addition of MPA, but was not induced by MPA alone. Tamoxifen induced ER and PR but not Ki-67 expression or glandular hyperplasia. Neoplasms were not seen. These findings indicate that progestogens(MPA) may exacerbate, not antagonize mammary gland proliferation induced by estrogen replacement therapy, and that tamoxifen has both estrogen agonist and antagonist effects on sex steroid receptor expression in the normal primate breast.

1999 – Benign breast biopsies from 86 post menopausal women

Hofseth, Lorne J., et al. “Hormone replacement therapy with estrogen or estrogen plus medroxyprogesterone acetate is associated with increased epithelial proliferation in the normal postmenopausal breast.” The Journal of Clinical Endocrinology & Metabolism 84.12 (1999): 4559-4565.

The relative effects of postmenopausal hormone replacement therapy (HRT) with estrogen alone vs. estrogen+progestin on breast cell proliferation and on breast cancer risk are controversial. A cross-sectional observational study was carried out to examine the proliferative effects of HRT with estrogen or estrogen plus the progestin, medroxyprogesterone acetate, in breast tissue of postmenopausal women.

Benign breast biopsies from 86 postmenopausal women
were analyzed with antiproliferating cell nuclear antigen (anti-PCNA) and Ki67 antibodies to measure relative levels of cell proliferation. Epithelial density and estrogen and progesterone receptor status were also determined. The women were categorized either as users of:
1) estrogen (E) alone;(Premarin)
2) estrogen+medroxyprogesterone acetate (E+P); or
3) no HRT.

Compared with no HRT, the breast epithelium of women who had received either E+P or E alone had significantly higher PCNA proliferation indices, and treatment with E+P had a significantly higher index (PCNA and Ki67) than treatment with E alone.

Breast epithelial density was significantly greater in postmenopausal women treated with E and E+P, compared with no HRT. Thus, the present study shows that postmenopausal HRT with E+P was associated with greater breast epithelial cell proliferation and breast epithelial cell density than E alone or no HRT. Furthermore, with E+P, breast proliferation was localized to the terminal duct-lobular unit of the breast, which is the site of development of most breast cancers. Further studies are needed to assess the possible association between the mitogenic activity of progestins and breast cancer risk.

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Estriol

7) Head, Kathleen A. “Estriol: safety and efficacy.Alternative medicine review: a journal of clinical therapeutic 3.2 (1998): 101-113.

Abstract While conventional hormone replacement therapy provides certain benefits, it is not without significant risks. Estriol has been found to provide some of the protection without the risks associated with stronger estrogens. Depending upon the situation, estriol may exert either agonistic or antagonistic effects on estrogen. Estriol appears to be effective at controlling symptoms of menopause, including hot flashes, insomnia, vaginal dryness, and frequent urinary tract infections. Results of research on its bone-density-maintaining effects have been contradictory, with the most promising results coming from Japanese studies. Estriol’s effect on cardiac risk factors has also been somewhat equivocal; however, unlike conventional estrogen prescriptions, it does not seem to contribute to hypertension. Although estriol appears to be much safer than estrone or estradiol, its continuous use in high doses may have a stimulatory effect on both breast and endometrial tissue.

increasing durable resistance to carcinogenesis.

8) Lemon, Henry M. “Antimammary carcinogenic activity of 17‐alpha‐ethinyl estriol.Cancer 60.12 (1987): 2873-2881.

Abstract Both initiation and promotion of dimethylbenz(a)anthracene (DMBA)-induced mammary carcinogenesis were inhibited by prophylactic therapy for 1 to 7 months using 17-alpha-ethinyl-estriol in doses as low as 1.0 microgram/d administered to intact virgin female Sprague-Dawley rats at 35 to 65 days of age. Administration of 638-micrograms single or multiple doses 2 to 3 weeks before DMBA induced a 75% to 85% reduction in cancer incidence after 1 year (P less than 0.001). When treatment was begun 2 weeks after DMBA, 1.0 microgram/d infused for 84 days resulted in a 44% reduction in incidence, with higher-dose, more prolonged therapy achieving a 73% reduction, equal to the reduction in carcinoma incidence observed after ovariectomy. Biopsies of nontumorous mammary glands showed a positive correlation between prelactational lobuloalveolar hyperplasia, hormone dose, and reduction in incidence of mammary carcinoma. Similar treatment with 17-alpha-ethinyl-estradiol-17B and diethylstilbestrol did not inhibit the 90% to 100% incidence of carcinoma observed in DMBA-treated control rats, and induced lactational hyperplasia in mammary gland biopsies. Continuous ethinyl estriol infusion subcutaneous (sc) in 2.5 to 7.5 micrograms daily dosage significantly increased uterine weights by as much as 10% to 46% after 2 to 4 weeks. At the time of mammary neoplasm development when rats were necropsied, no significant difference was observed in uterine weights between rats receiving 638 micrograms/mo in a readily soluble pellet implant, and uterine weights of control rats. Ethinyl estriol given seven times monthly in 638-micrograms bolus doses was more inhibitory of mammary carcinogenesis than estriol after a year (P less than 0.1 greater than 0.05). Short-term intermittent administration of ethinyl estriol to young nulliparous women may offer a method of simulating the differentiating effect of pregnancy on mammary tissues, increasing durable resistance to carcinogenesis.

9) Lemon, Henry M. “Pathophysiologic considerations in the treatment of menopausal patients with oestrogens; the role of oestriol in the prevention of mammary carcinoma.Acta endocrinologica. Supplementum 233 (1980): 17-27.

At menopause, several abnormalities in oestrogen metabolism have been reported, which may increase the likelihood of cancer development in the breast or uterus following oestrone or oestradiol-17 beta supplementation. Occult hypothyroidism reduces the rate of oestrogen inactivation by C2 hydroxylation, and 15-20% of women have low rates of C16 hydroxylation to oestriol. Reduced sex hormone binding globulin concentration occurs in association with obesity, thereby increasing the biologically active unbound fraction of oestradiol in plasma. Since oestriol undergoes minimal metabolism after absorption, does not bind to sex hormone binding globulin, and has an anti-oestradiol action by decreasing the duration of nuclear binding of oestradiol-receptor proteins, it is less likely to induce proliferative changes in target organs of cancer-prone women than oestrone or oestradiol. Intermittent non-conjugated oestriol treatment has demonstrated the most significant anti-mammary carcinogenic activity of 22 tested compounds as well as anti-uterotropic activity in intact female Sprague Dawley rats fed either of two dissimilar carcinogens (7, 12 dimethylbenz(a) anthracene, procarbazine) and followed for their natural life span. The protective effect was specific for mammary carcinomas only and has been decreased in rats with a 20% increase in growth curves. Clinical experience thus far with oral oestriol therapy of post-menopausal women has indicated little hazard of cancer development.

10) Lemon, H. M. “Clinical and experimental aspects of the anti-mammary carinogenic activity of estriol.Frontiers of Hormone Research 5 (1977): 155-173.

Abstract Intermittent implantation of 600–1,300 microgram estriol subcutaneously beginning 48 h before oral administration of 7,12-dimethylbenz(a)anthracene or procarbazine prevents development of 80–90% of carcinomas of the breast occurring during the natural life span of the intact female Sprague-Dawley rat. Some estriol precursors were less inhibitory of breast cancer development among 23 other estrogens and androgens, progestins and glucocorticoids tested. More frequent or lower estriol doses than 100–200 microgram/kg/24 h every 2 months were less inhibitory of breast carcinogenesis. No other types of neoplasms were reduced in incidence by estriol implants, which also reduced uterine weights by 20–25%. Intermittent substitution of estriol for estrone or estradiol in the nuclear receptor complexes of target cells probably accounts for these observations, which resemble the effect of castration in reducing breast cancer incidence. Human studies indicate excellent tolerance for oral estriol doses of 10–200 microgram/kg/24 h, which may correct subnormal estriol/estrone + estradiol urinary quotients associated with elevated risk of breast carcinogenesis in epidemiologic investigations.

11 ) Lemon, Henry M. “Estriol prevention of mammary carcinoma induced by 7, 12-dimethylbenzanthracene and procarbazine.” Cancer Research 35.5 (1975): 1341-1353.

Abstract
The concentration of estrogenic, androgenic, progestational, and adrenocortical steroid hormones in body fluids of mature intact Sprague-Dawley female rats was increased by s.c. implantation of 5 to 7 mg NaCl pellets containing 1 to 20% steroid 48 hr before administration p.o. of either 7,12-dimethylbenz(a) anthracene or procarbazine.

The incidence of rats developing one or more mammary carcinomas in each treated group was compared to that observed in simultaneously treated groups receiving only the carcinogen, steroid, or no treatment whatsoever, with weekly observation of all rats until palpably growing tumors were biopsied and proven carcinomatous or until death occurred from other causes determined by autopsy. A total of 105 untreated or steroid-implanted rats followed to death (234 to 256 days median observation) developed no breast carcinomas. Rats fed either of the carcinogens developed initial evidence of breast carcinoma, after 136 to 156 days median observation, in 51 to 57% of 318 total treated rats. Nonbreast carcinomas and sarcomas developed in 5 to 10% of the carcinogen-treated rats.

 

E3 was administered in various dosages (2, 4, 6, and 8 mg/d) to 52 symptomatic post-menopausal women as oestrogen replacement therapy for a six-month period.

12) Tzingounis, V. A., M. Feridun Aksu, and R. B. Greenblatt. “The significance of oestriol in the management of the post-menopause.” Acta endocrinologica. Supplementum 233 (1980): 45-50.

Abstract Oestrogen replacement therapy relieves many post-menopausal symptoms and has been successfully employed clinically for this purpose for more than four decades. Recently the alleged relationship between oestrogens and cancer has stimulated a re-evaluation of an old oestrogen preparation, oestriol (E3). The dosages of E3 employed appear to vary considerably, and the need was felt to establish the dosage on a scientific basis. Accordingly in the study reported here E3 was administered in various dosages (2, 4, 6, and 8 mg/d) to 52 symptomatic post-menopausal women as oestrogen replacement therapy for a six-month period. Assays of follicle-stimulating hormone (FSH), luteinizing hormone (LH), oestrone (E1) and oestradiol (E2) were performed before and during therapy and vaginal cytology, cervical mucus and endometrial studies were performed during the period of administration. The clinical effectiveness of E3 was found to be directly related to dosage. E3 did not induce endometrial proliferation and proved a poor suppressor of FSH and LH. The ability of oestriol to relieve vasomotor instability and to improve vaginal maturation without inducing notable side effects is sufficient reason for it to be included in the management of the post-menopausal syndrome.

12) Keller, P. J., et al. “Oestrogens, gonadotropins and prolactin after intra-vaginal administration of oestriol in post-menopausal women.” Maturitas 3.1 (1981): 47-53.

Abstract Serum total oestrone, 17 beta-oestradiol and oestriol concentrations and FSH, LH and prolactin values were measured radioimmunologically in post-menopausal women before and after intra-vaginal application of 0.5 mg oestriol. While oestrone and oestradiol were not altered, there was a 3100% increase in the mean oestriol values within 1 or 2 h; pre-treatment levels were again reached 8 h later. Both gonadotropins were moderately decreased, the serum prolactin values appeared to be slightly elevated. Repeated intra-vaginal application of oestriol resulted in a significant rise of the mean serum oestriol levels while the other oestrogens remained unchanged. The same was true for FSH and LH, a considerable negative feedback was therefore excluded. Again there seemed to be a slight rise of the prolactin secretion. It was concluded that intra-vaginal administration of oestriol is a most suitable local and systemic oestrogen replacement therapy, which is more effective than the oral regimen.

13) deleted
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1996 Dr Cline -Monkeys

14) Cline, J. Mark, et al. “Effects of hormone replacement therapy on the mammary gland of surgically postmenopausal cynomolgus macaques.” American journal of obstetrics and gynecology 174.1 (1996): 93-100.

Our purpose was to define the proliferative response and receptor status in the mammary glands of surgically postmenopausal macaques given hormone replacement therapy, equivalent for monkeys to that given women.

STUDY DESIGN:Surgically postmenopausal adult female cynomolgus macaques (Macaca fascicularis) were given either :

no treatment (n = 26),
conjugated equine estrogens (n = 22), or
combined therapy with conjugated equine estrogens and medroxyprogesterone acetate (n = 21).

Drugs were administered in the diet, at doses equivalent on a caloric basis to 0.625 mg per woman per day for conjugated equine estrogens and 2.5 mg per woman per day for medroxyprogesterone acetate, for 30 months.

Mammary gland proliferation was assessed subjectively and by morphometric and stereologic means. Estrogen receptor and progesterone receptor content and proliferation were studied by immunohistochemistry.

RESULTS: In this model combined therapy with conjugated equine estrogens and medroxyprogesterone acetate induced greater proliferation than did conjugated equine estrogens alone. The percentage of estrogen receptor-positive cells was decreased in the conjugated equine estrogens plus medroxyprogesterone acetate group. The percentage of progesterone receptor-positive cells was increased by treatment with conjugated equine estrogens alone.

CONCLUSION: These results indicate a proliferative response of mammary gland epithelium to therapy with conjugated equine estrogens plus medroxyprogesterone acetate in postmenopausal macaques. The clinical implication of this finding may be a greater risk for development of breast neoplasms in women receiving combined hormone replacement therapy.

“when in fact, it [WHI] did not study hormone replacement at all: that would have required use of the natural hormones, estradiol and progesterone.”

15) Bethea, Cynthia L. “MPA: M edroxy-P rogesterone A cetate Contributes to M uch P oor A dvice for Women.” (2011): 343-345.

Dr. Cynthia L. Bethea, Oregon National Primate Research Center, Reproductive Sciences and Neuroscience, 505 Northwest 185th Avenue, Beaverton, Oregon.

While the WHI trial made a valuable contribution in revealing the risks associated with conjugated equine estrogens plus MPA 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.” The Irwin et al. (3) study focuses on the progestin problem.

progesterone has potent neuroprotective effects and MPA does not.

We found that in nonhuman primates, estradiol or equine estrogens increase the expression of tryptophan hydroxylase (TPH), the rate-limiting enzyme in serotonin synthesis. Supplementation with progesterone was neutral and TPH remained elevated (, ). In contrast, supplementation with MPA completely blocked the effect of equine estrogens (). Thus, MPA endangers brain cells and potentially facilitates stress and depression.

MPA reduces the dilatory effect of estrogens on coronary arteries, increases the progression of coronary artery atherosclerosis, accelerates low-density lipoprotein uptake in plaque, increases the thrombogenic potential of atherosclerotic plaques, and promotes insulin resistance and its consequent hyperglycemia in primates (), whereas progesterone does not

Most of the research papers showing significantly better outcomes in brain, breast, and cardiovascular parameters with estradiol plus progesterone instead of MPA end with rational statements to the effect that hopefully the data will lead to better hormone therapy. Is hope overcoming hype? Perhaps (, ); but many physicians remain under the misapprehension that all progestins are alike.

1998 Dr Russo – Career Based on Estrogen Causes of Breast Cancer

16) Russo, Irma H., and Jose Russo. “Role of hormones in mammary cancer initiation and progression.Journal of mammary gland biology and neoplasia 3 (1998): 49-61.

Breast cancer, the most frequent spontaneous malignancy diagnosed in women in the Western world, is a classical model of hormone dependent malignancy. There is substantial evidence that breast cancer risk is associated with prolonged exposure to female hormones, since early onset of menarche, late menopause, hormone replacement therapy and postmenopausal obesity are associated with greater cancer incidence. Among these hormonal influences a leading role is attributed to estrogens, either of ovarian or extra-ovarian origin, as supported by the observations that breast cancer does not develop in the absence of ovaries, ovariectomy causes regression of established malignancies, and in experimental animal models estrogens can induce mammary cancer. Estrogens induce in rodents a low incidence of mammary tumors after a long latency period, and only in the presence of an intact pituitary axis, with induction of pituitary hyperplasia or adenomas and hyperprolactinemia.

Chemicals, radiation, viruses and genomic alterations have all been demonstrated to have a greater tumorigenic potential in rodents.

Chemical carcinogens are used to generate the most widely studied rat models; in these models hormones act as promoters or inhibitors of the neoplastic process. The incidence and type of tumors elicited, however, are strongly influenced by host factors. “The tumorigenic response is maximal when the carcinogen is administered to young and virgin intact animals in which the mammary gland is undifferentiated and highly proliferating. “The atrophic mammary gland of hormonally-deprived ovariectomized or hypophysectomized animals does not respond to the carcinogenic stimulus.

Administration of carcinogen
to pregnant, parous or hormonally treated virgin rats, on the other hand, fails to elicit a tumorigenic response, a phenomenon attributed to the higher degree of differentiation of the mammary gland induced by the hormonal stimulation of pregnancy. In women a majority of breast cancers that are initially hormone dependent are manifested during the postmenopausal period. Estradiol plays a crucial role in their development and evolution. However, it is still unclear whether estrogens are carcinogenic to the human breast.”

The apparent carcinogenicity of estrogens is attributed to receptor-mediated stimulation of cellular proliferation. Increased proliferation could result in turn in accumulation of genetic damage and stimulation of the synthesis of growth factors that act on the mammary epithelial cells via an autocrine or paracrine loop.

….reaction of specific estrogen metabolites, namely, catechol estrogen-3,4-quinones (CE-3,4-Q) and to a much lesser extent, CE-2,3-Q, can generate critical DNA mutations that initiate breast, prostate and other cancers…

17) 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.

Conclusions: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.2007 the estrogen paradox

At menopause E2 plasma levels decrease by 90%.

…Reaction of specific estrogen metabolites, namely, catechol estrogen-3,4-quinones (CE-3,4-Q) and to a much lesser extent, CE-2,3-Q, can generate critical DNA mutations that initiate breast, prostate and other cancers

 

17B) Cavalieri, E. L., et al. “Molecular origin of cancer: catechol estrogen-3, 4-quinones as endogenous tumor initiators.” Proceedings of the National Academy of Sciences 94.20 (1997): 10937-10942.

oxidation of the carcinogenic 4-hydroxy catechol estrogens (CE) of estrone (E1) and estradiol (E2) to catechol estrogen-3,4-quinones (CE-3, 4-Q) results in electrophilic intermediates that covalently bind to DNA to form depurinating adducts. The resultant apurinic sites in critical genes can generate mutations that may initiate various human cancers.

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The Estrogen Paradox

18) Santen, Richard J. “The oestrogen paradox: a hypothesis.Endokrynologia Polska 58.3 (2007): 222-227.

The initial publication of the Women’s Health Initiative (WHI) [3] reported a 23% decrease in invasive breast cancer incidence in patients taking oestrogen alone compared with placebo, a finding which narrowly fell short of statistical significanceand a 33% reduction in invasive breast cancer incidence in patients who strictly adhered to their oestrogen therapy (HR 0.67, 95% CI 0.47 to 0.97).

A second component of the oestrogen paradox is that women with hormone-dependent breast cancer respond to high-dose oestrogens with objective tumour regressions. This form of therapy was the mainstay of hormonal treatment of breast cancer from the late 1940s until the early 1980s [79]. When compared in randomized trials with tamoxifen, high-dose oestrogens were equally efficacious [7] and in one study they were associated with significantly enhanced survival [8] compared with an anti-oestrogen.

shown in Figure ​1, a wide range of epidemiologic and observational data suggest that oestrogens are associated with the development of breast cancer [1,2]. With these data as a background, it was quite surprising that recently published data suggested that women taking postmenopausal hormone therapy (MHT) with oestrogen alone for 5 to 9 years unexpectedly experienced a decrease in the risk for breast cancer [3,4]. However, when taken for more than 20 years, the risk appeared to increase [5,6]. We call this the ‘oestrogen paradox’ to highlight the fact that short-term oestrogen use decreases the risk for breast cancer whereas long-term use increases it.

A second component of the oestrogen paradox is that high-dose oestrogen therapy in postmenopausal women with breast cancer causes tumour regression, whereas the anti-oestrogen tamoxifen is equally effective in causing remissions in similar patient groups [7-9].

Extensive studies demonstrated that only specific subgroups of women respond to high-dose oestrogen [9, 12]. Premenopausal women and those less than 1 year postmenopausal do not respond at all. Women who had undergone menopause many years earlier frequently experienced objective tumour regressions; the longer the duration of the period after cessation of menses, the greater the response rate. Only oestrogen receptor (ER)-positive tumours regress in women receiving high-dose oestrogens [12].

“It is paradoxical then that both oestrogens and anti-oestrogens cause tumour regressions.”

Our preclinical data demonstrate that long-term deprivation of oestradiol causes this sex steroid to trigger cell death through apoptosis.

The postmenopausal women receiving MHT with oestrogen alone may be considered to be in a state of long-term oestradiol deprivation. Extensive review of autopsy studies provides strong evidence that there is a reservoir of undiagnosed breast cancer in postmenopausal women (Table 1) [22, 23]. The short-term reduction in breast cancer in the patients with undiagnosed occult breast tumours may be due to oestrogen-induced apoptosis of tumour cells. Similarly, the effect of oestrogen in inducing tumour regressions in patients with known breast cancer may reflect a similar phenomenon.

Recent in vitro studies from our laboratory showed that hormone-dependent breast cancer cells deprived of oestrogen in the long term undergo adaptive changes that cause oestrogen to paradoxically stimulate apoptosis [1315] (Figure 2a).

Similarly, Jordan and collaborators [1621] demonstrated that long-term tamoxifen exposure also results in adaptation and development of oestrogen-induced apoptosis. Apoptotic mechanisms in adapted cells involve upregulation of death receptor as well as mitochondrial pathways. Specific molecular events include activation of the Fas death receptor/Fas ligand complex, the release of cytochrome C from the mitochondria, alterations in Bcl-2, and downregulation of the anti-apoptotic factor nuclear factor-κ [14, 15, 18].

Long-term exposure to oestradiol

Why would oestrogen increase the risk for breast cancer when it is given for more than 20 years? The commonly accepted explanation for the carcinogenic effect of oestrogen is that this sex steroid stimulates breast cancer proliferation genes, increases the rate of breast cell divisions, and thereby enhances the chances for development of mutations [25]. An additional and more controversial mechanism suggests that metabolites of oestradiol are directly genotoxic [24, 25] (Figure 3). Recent studies demonstrate that oestradiol is converted to 4-OH-oestradiol in human breast tissue via the cytochrome p450 1B1 enzyme, and it is then oxidized to quinone metabolites. These metabolites are highly reactive and covalently bind to adenine and guanine on DNA, resulting in depurination, error-prone DNA repair, and point mutations [24]. Other recent studies have shown that 4-OH-oestradiol is directly mutagenic in cellular mutagenesis assays [2629]. In addition, 4-OH-oestradiol can transform ER-negative benign breast epithelial cells into serially transplantable carcinomas in immune deficient mice [28]. Finally, an ER knockout model of breast cancer forms tumours in response to increasing doses of exogenous oestradiol in previously castrated animals [24, 30]. These combined observations suggest that directly genotoxic as well as ER-mediated mechanisms may be responsible for the long-term carcinogenic effects of oestradiol [24].

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Progesterone Reduces Breast Cell Proliferation Caused By Estrogen

19) Chang, King-Jen, et al. “Influences of percutaneous administration of estradiol and progesterone on human breast epithelial cell cycle in vivo.” Fertility and sterility 63.4 (1995): 785-791.

To study the effect of E2 and P on the epithelial cell cycle of normal human breast in vivo.
DESIGN: Double-blind, randomized study. Topical application to the breast of a gel containing either a placebo, E2, P, or a combination of E2 and P, daily, during the 10 to 13 days preceding breast surgery.
PATIENTS : Forty premenopausal women undergoing breast surgery for the removal of a lump. MAIN OUTCOME MEASURES. Plasma and breast tissue concentrations of E2 and P. Epithelial cell cycle evaluated in normal breast tissue areas by counting mitoses and proliferating cell nuclear antigen immunostaining quantitative analyses.
RESULTS: Increased E2 concentration increases the number of cycling epithelial cells. Increased P concentration significantly decreases the number of cycling epithelial cells.
CONCLUSION: Exposure to P for 10 to 13 days reduces E2-induced proliferation of normal breast epithelial cells in vivo.

20) Jean-Michel Foidart, M. D., et al. “Estradiol and progesterone regulate the proliferation of human breast epithelial cells.” Fertility and Sterility 69.5 (1998): 963-969.

DESIGN: Double-blind randomized study.
SETTING: Departments of gynecology and of cell biology at a university hospital.
PATIENT(S): Forty postmenopausal women with untreated menopause and documented plasma FSH levels of >30 mIU/mL and estradiol levels of <20 pg/mL.
INTERVENTION(S): Daily topical application to both breasts of a gel containing a placebo, estradiol, progesterone, or a combination of estradiol and progesterone during the 14 days preceding esthetic breast surgery or excision of a benign lesion.
MAIN OUTCOME MEASURE(S): Plasma and breast tissue concentrations of estradiol and progesterone. Epithelial cell cycles were evaluated in normal breast tissue by counting mitoses and performing quantitative proliferating cell nuclear antigen immunolabeling analyses.
RESULT(S): Increasing the estradiol concentration enhanced the number of cycling epithelial cells, whereas increasing the progesterone concentration significantly limited the number of cycling epithelial cells.
CONCLUSION(S): Exposure to progesterone for 14 days reduced the estradiol-induced proliferation of normal breast epithelial cells in vivo.
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ER Beta Inhibits Carcinogenesis-
ERbeta inhibits proliferation by repressing c-myc, cyclin D1, and cyclin A gene transcription, and increasing the expression of p21(Cip1) and p27(Kip1), which leads to a G(2) cell cycle arrest.

21) Paruthiyil, Sreenivasan, et al. “Estrogen receptor β inhibits human breast cancer cell proliferation and tumor formation by causing a G2 cell cycle arrest.Cancer research 64.1 (2004): 423-428.

Studies indicate that estrogen receptor (ER) alpha mediates breast cancer-promoting effects of estrogens. The role of ERbeta in breast cancer is unknown. Elucidating the role of ERbeta in the pathogenesis of breast cancer is important because many human breast tumors express both ERalpha and ERbeta. We show that adenovirus-mediated expression of ERbeta changes the phenotype of ERalpha-positive MCF-7 cells. Estradiol increases cell proliferation and causes tumor formation of MCF-7 cells expressing only ERalpha. In contrast, introducing ERbeta into MCF-7 cells causes an inhibition of proliferation in vitro and prevents tumor formation in a mouse xenograft model in response to estradiol. ERbeta inhibits proliferation by repressing c-myc, cyclin D1, and cyclin A gene transcription, and increasing the expression of p21(Cip1) and p27(Kip1), which leads to a G(2) cell cycle arrest.

These results demonstrate that ERalpha and ERbeta produce opposite effects in MCF-7 cells on cell proliferation and tumor formation. Natural or synthetic ER beta-selective estrogens may lack breast cancer promoting properties exhibited by estrogens in hormone replacement regimens and may be useful for chemoprevention of breast cancer.

22) Warner, Margaret, and Jan-Åke Gustafsson. “The role of estrogen receptor β (ERβ) in malignant diseases—A new potential target for antiproliferative drugs in prevention and treatment of cancer.” Biochemical and biophysical research communications 396.1 (2010): 63-66.

Abstract The discovery of ERbeta in the middle of the 1990s represents a paradigm shift in our understanding of estrogen signaling. It has turned out that estrogen action is not mediated by one receptor, ERalpha, but by two balancing factors, ERalpha and ERbeta, which are often antagonistic to one another. Excitingly, ERbeta has been shown to be widespread in the body and to be involved in a multitude of physiological and pathophysiological events. This has led to a strong interest of the pharmaceutical industry to target ERbeta by drugs against various diseases. In this review, focus is on the role of ERbeta in malignant diseases where the anti proliferative activity of ERbeta gives hope of new therapeutic approaches.

23) Zhu, Bao Ting. “Is it necessary to control the level of estrogen receptor α and β activation in postmenopausal hormone replacement therapy in order to achieve the optimal outcome?.” Molecular Medicine Reports 1.1 (2008): 15-20.

Abstract : Endogenous estrogens exert an array of biological actions on women, many of which are mediated by the estrogen receptors (ERs) α and β. Results from our recent studies suggest that the human ERα and ERβ systems are differentially activated under different physiological conditions. In non-pregnant young women, the ERα system is preferentially activated over the ERβ system, mainly by estrone (E1) and its major oxidative metabolite, 2-hydroxy-E1. These two estrogens are among the quantitatively major estrogens present in young women, and have approximately 4-fold preferential activity for ERα over ERβ. During pregnancy, however, there is a preponderance of activation of ERβ over ERα conferred by various pregnancy estrogens such as estriol and other D-ring derivatives of 17β-estradiol (E2). These estrogens have an up to 18-fold preference for binding to ERβ than for ERα, and some of them are produced in unusually large quantities. Given this new information, it is hypothesized that the estrogens ideal for female hormone replacement therapy (HRT) would be those which produce a hormonal condition mirroring that found in non-pregnant young women rather than in pregnant women. Endogenous estrogen derivatives, such as the sulfated conjugates of E1, may be among the ideal candidates for achieving this clinical purpose. In comparison, Premarin, the most commonly-used HRT containing a mixture of conjugated estrogens isolated from pregnant mare’s urine, is less suitable because several of its estrogenic components can produce a strong preferential over-stimulation of the human ERβ signaling system.

24) Zhu, Bao Ting, et al. “Quantitative structure-activity relationship of various endogenous estrogen metabolites for human estrogen receptor α and β subtypes: Insights into the structural determinants favoring a differential subtype binding.Endocrinology 147.9 (2006): 4132-4150.

To search for endogenous estrogens that may have preferential binding affinity for human estrogen receptor (ER) alpha or beta subtype and also to gain insights into the structural determinants favoring differential subtype binding, we studied the binding affinities of 74 natural or synthetic estrogens, including more than 50 steroidal analogs of estradiol-17beta (E2) and estrone (E1) for human ER alpha and ER beta. Many of the endogenous estrogen metabolites retained varying degrees of similar binding affinity for ER alpha and ER beta, but some of them retained differential binding affinity for the two subtypes. For instance, several of the D-ring metabolites, such as 16 alpha-hydroxyestradiol (estriol), 16 beta-hydroxyestradiol-17 alpha, and 16-ketoestrone, had distinct preferential binding affinity for human ER beta over ER alpha (difference up to 18-fold). Notably, although E2 has nearly the highest and equal binding affinity for ER alpha and ER beta, E1 and 2-hydroxyestrone (two quantitatively predominant endogenous estrogens in nonpregnant woman) have preferential binding affinity for ER alpha over ER beta, whereas 16 alpha-hydroxyestradiol (estriol) and other D-ring metabolites (quantitatively predominant endogenous estrogens formed during pregnancy) have preferential binding affinity for ER beta over ER alpha.

Estrogen Benefits for Reversing Atherosclerosis

25) Mikkola, Tomi S., and Thomas B. Clarkson. “Estrogen replacement therapy, atherosclerosis, and vascular function.” Cardiovascular research 53.3 (2002): 605-619.

There is strong evidence from both human and nonhuman primate studies supporting the conclusion that estrogen deficiency increases the progression of atherosclerosis. More controversial is the conclusion that postmenopausal estrogen replacement inhibits the progression of atherosclerosis. Estrogen treatment of older women (>65 years) with pre-existing coronary artery atherosclerosis had no beneficial effects. In contrast, estrogen treatment of younger postmenopausal women or monkeys in the early stages of atherosclerosis progression has marked beneficial effects. Whether progestogens attenuate the cardiovascular benefits of estrogen replacement therapy has been controversial for more than a decade. Current evidence from studies of both monkeys and women suggest little or no attenuation of estrogen benefits for coronary artery atherosclerosis. Lack of compliance with estrogen replacement therapy, usually because of fear of breast cancer, remains a major problem.

Testosterone Inhibits Estrogen Induced Breast Cell Epithelial Proliferation

26) Zhou, Jian, et al. “Testosterone inhibits estrogen‐induced mammary epithelial proliferation and suppresses estrogen receptor expression.” The FASEB Journal 14.12 (2000): 1725-1730.

27) see (21) this is a duplicate

Compounded HRT Improves Mood

28) Ruiz, Andres D., et al. “Effectiveness of compounded bioidentical hormone replacement therapy: an observational cohort study.” BMC women’s health 11 (2011): 1-10.

Women experienced a 25% decrease in emotional lability (p < 0.01), a 25% decrease in irritability (p < 0.01), and a 22% reduction in anxiety (p = 0.01) within 3 to 6 months.

See Table 1 for Typical Compounded HRT Dosing

Dose Classification     Dose Range  

Topical Estrogen

Low Dose  ≤0.5 mg

Moderate Dose 0.51-1 mg

High Dose >1 mg

Oral Estrogen

Low Dose ≤1 mg

Moderate Dose 1.1-2 mg

High Dose >2 mg

Topical Progesterone

Low Dose <20 mg

Moderate Dose 21-50 mg

High Dose >50 mg

Oral Progesterone

Low Dose <100 mg

Moderate Dose 101-200 mg

High Dose >200 mg

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