Transdermal vs. Oral Estrogen Part Two by Jeffrey Dach MD

Transdermal vs. 

Oral Estrogen Part Two 

by Jeffrey Dach MD

In part one, we explored the studies which show that transdermal estrogen delivery is preferable over the oral pill form of delivery.  In part two of this series, we will explore further the studies which explain why oral estrogen pills are associated with a hypercoagulability and inflammation causing the observed increase in clots, deep venous thrombosis, pulmonary embolus, and stroke in young women on “the Pill” and in post-menopausal women on oral HRT.(1,7)  Transdermal estrogen on the other hand does not cause such effects, making it the safer choice. (1)

Above left image : Premarin and Prempro are the two most common oral estrogen pills known to cause blood clot formation. Poster courtesy of Tuesday Horse Files.

Bioidentical HRT- Comparing Oral Vs. Transdermal Estrogen

In 1997, Dr. Scarabin studied bioidentical HRT in post menopausal women.  He compared oral to transdermal estrogen delivery in 45 post-menopausl women in Paris France.  The women were given either oral or transdermal estradiol, along with natural progesterone, and various parameters of the coagulation system were studied.

Dr Scarabin concluded: “that oral estrogen/progesterone replacement therapy may result in coagulation activation and increased fibrinolytic potential, whereas opposed transdermal estrogen appears without any substantial effects on hemostasis.” (1)

Avoiding Hepatic First Pass Metabolism

In a 2009 report, Dr Kopper speculates that transdermal is safer and more effective than oral.  He says:

“Transdermal drug delivery may mitigate some of these effects by avoiding gut and hepatic first-pass metabolism. Advantages of transdermal delivery include the ability to administer unmetabolized estradiol directly to the blood stream, administration of lower doses compared to oral products, and minimal stimulation of hepatic protein production.”(2)

CRP Goes Up with Oral Estrogen

Published in 2002 in Circulation, Dr Decensi from Milan Italy studied changes in CRP in 189 postmenopausal women randomized to either oral CEE(Premarin)/provera or to transdermal Estradiol/provera.(3)

Left Image Prempro pack known to cause blood clots,   courtesy of Wyeth, Pfizer.

CRP is a non-specific inflammatory marker which increases risk for heart disease.

After 12 months, the Prempro treated women had a 64% increase in CRP.  The Transdermal estradiol/provera combination had only 3% increase in CRP.(3)

A second report published in 2008 by the Milan Group on the same patient group showed a significant effect on fibrinogen levels.(4)  The oral estrogen group had a 5-fold decrease in fibrinogen for oral pills (Prempro) compared to transdermal estrogen, ( -5.7% vs, -1.1%)  Reduction in fibrinogen levels indicate activation of the clotting system, with consumption of clotting factors faster than synthesis.(4)

More on CRP by Dr. Koh

Dr Koh published his observations in 2006 Cardiovascular Research in which he reviewed the medical literature and remarks:(6)

“Orally administered estrogens increase blood CRP levels and maintain sustained increases for up to 3 years . By contrast, transdermal estradiol in healthy postmenopausal women significantly lowers CRP levels, or remains unchanged.  In premenopausal women, CRP correlates inversely with blood estradiol concentrations during the menstrual cycle.” (6)

Oral Estrogen Increased Markers of Hypercoagulability

Published in 2001, Dr Vehkavaarafrom Helsinki Finland studied 27 post-menopausal women on either oral or transdermal estrogen.  They found oral estrogen increased markers of hypercoagulability and CRP, while transdermal estrogen had no such effects.(5)

“oral estradiol changed markers of coagulation towards hypercoagulability, and increased serum CRP concentrations. Transdermal estradiol or placebo had no effects on any of these parameters.”(5) 

Conclusion:

There is overwhelming evidence in the medical literature that oral estrogen increases markers of hypercoagilbility(7) and CRP, while transdermal estrogen has no such deleterious effects.

Links and References:

1) http://atvb.ahajournals.org/content/17/11/3071.long

http://www.ncbi.nlm.nih.gov/pubmed/9409295

Effects of oral and transdermal estrogen/progesterone regimens on blood coagulation and fibrinolysis in postmenopausal women. A randomized controlled trial. Scarabin PY, Alhenc-Gelas M, Plu-Bureau G, Taisne P, Agher R, Aiach M.

SourceINSERM-Cardiovascular Epidemiology Unit U258, Hôpital Broussais, Paris, France  Abstract

Postmenopausal hormone replacement therapy is associated with a reduction in the incidence of coronary heart disease. However, inconclusive results have been reported with respect to the risk of stroke, and recent studies consistently showed an increased risk of venous thromboembolism in postmenopausal women using oral estrogen. There are surprisingly few interventional studies to assess the true effects of estrogen-progestin regimens on blood coagulation and fibrinolysis, and the impact of the route of estrogen administration on hemostasis has not been well documented.

Therefore, we investigated the effects of oral and transdermal estradiol/progesterone replacement therapy on hemostatic variables. Forty-five healthy postmenopausal women, aged 45 to 64 years, were assigned randomly to one of the three following groups: cyclic oral or transdermal estradiol, both combined with progesterone, or no hormonal treatment. Hemostatic variables were assayed at baseline and after a 6-month period. Pairwise differences in the mean change between the three groups were compared using nonparametric tests.

Oral but not transdermal estradiol regimen significantly increased the mean value of prothrombin activation peptide (F1 + 2) and decreased mean antithrombin activity compared with no treatment. Differences in fragment F1 + 2 levels between active treatments were significant.

The oral estrogen group was associated with a significant decrease in both mean tissue-type plasminogen (t-PA) concentration and plasminogen activator inhibitor (PAI-1) activity and a significant rise in global fibrinolytic capacity (GFC) compared with the two other groups.

A transdermal estrogen regimen had no significant effect on PAI-1, t-PA, and GFC levels. There were no significant changes in mean values of fibrinogen, factor VII, von Willebrand factor, protein C, fibrin D-dimer, and plasminogen between and within the three groups.

We conclude that oral estrogen/progesterone replacement therapy may result in coagulation activation and increased fibrinolytic potential, whereas opposed transdermal estrogen appears without any substantial effects on hemostasis. Whereas these results may account for an increased risk of venous thromboembolism in users of oral postmenopausal estrogen, they emphasize the potential importance of the route of estrogen administration in prescribing hormone replacement therapy to postmenopausal women, especially to those at high risk of thrombotic disease.

2) http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2761184/

http://www.ncbi.nlm.nih.gov/pubmed/19920906

Drug Des Devel Ther. 2009 Feb 6;2:193-202.

Transdermal hormone therapy in postmenopausal women: a review of metabolic effects and drug delivery technologies. Kopper NW, Gudeman J, Thompson DJ.

Source KV Pharmaceutical, 2503 South Hanley Road, St. Louis, MO 63144, USA.

Abstract Vasomotor symptoms (VMS) associated with menopause can cause significant discomfort and decrease the quality of life for women in the peri-menopausal and post-menopausal stages of life. Hormone therapy (HT) is the mainstay of treatment for menopausal symptoms and is currently the only therapy proven effective for VMS. Numerous HT options are available to treat VMS, including estrogen-only and estrogen-progestogen combination products to meet the needs of both hysterectomized and nonhysterectomized women. In addition to selecting an appropriate estrogen or estrogen-progestogen combination, consideration should be given to the route of administration to best suit the needs of the patient. Delivery systems for hormone therapy include oral tablets, transdermal patches, transdermal topical (nonpatch) products, and intravaginal preparations. Oral is currently the most commonly utilized route of administration in the United States. However, evidence suggests that oral delivery may lead to some undesirable physiologic effects caused by significant gut and hepatic metabolism. Transdermal drug delivery may mitigate some of these effects by avoiding gut and hepatic first-pass metabolism. Advantages of transdermal delivery include the ability to administer unmetabolized estradiol directly to the blood stream, administration of lower doses compared to oral products, and minimal stimulation of hepatic protein production. Several estradiol transdermal delivery technologies are available, including various types of patches, topical gels, and a transdermal spray.

3) http://www.ncbi.nlm.nih.gov/pubmed/12208797

Circulation. 2002 Sep 3;106(10):1224-8.

Effect of transdermal estradiol and oral conjugated estrogen on C-reactive protein in retinoid-placebo trial in healthy women. Decensi A, Omodei U, Robertson C, Bonanni B, Guerrieri-Gonzaga A, Ramazzotto F, Johansson H, Mora S, Sandri MT, Cazzaniga M, Franchi M, Pecorelli S.Division of Chemoprevention, European Institute of Oncology, Milan, Italy.

The increase in C-reactive protein (CRP) during oral conjugated equine estrogen (CEE) may explain the initial excess of cardiovascular disease observed in clinical studies. Because the effect of transdermal estradiol (E2) on CRP is unclear, we compared CRP changes after 6 and 12 months of transdermal E2 and oral CEE in a randomized 2×2 retinoid-placebo trial.

METHODS AND RESULTS: A total of 189 postmenopausal women were randomized to 50 microg/d transdermal E2 and 100 mg BID of the retinoid fenretinide (n=45), 50 microg/d transdermal E2 and placebo (n=49), 0.625 mg/d oral CEE and 100 mg BID fenretinide (n=46), or 0.625 mg/d oral CEE and placebo (n=49) for 1 year. Sequential medroxyprogesterone acetate was added in each group. Relative to baseline, CRP increased by 10% (95% CI -9% to 33%) and by 48% (95% CI 22% to 78%) after 6 months of transdermal E2 and oral CEE, respectively. The corresponding figures at 12 months were 3% (95% CI -14% to 23%) for transdermal E2 and 64% (95% CI 38% to 96%) for oral CEE.

CONCLUSIONS:

In contrast to oral CEE, transdermal E2 does not elevate CRP levels up to 12 months of treatment. The implications for early risk of coronary heart disease require further studies.

4)http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3234057/

http://www.ncbi.nlm.nih.gov/pubmed/22275964

Ecancermedicalscience. 2008;2:67. Feb 6.

The effect of transdermal estradiol or oral conjugated oestrogen and fenretinide versus placebo on haemostasis and cardiovascular risk biomarkers in a randomized breast cancer chemoprevention trial. Lazzeroni M, Macis D, Decensi A, Gandini S, Sandri MT, Serrano D, Guerrieri-Gonzaga A, Johansson H, Mora S, Daldoss C, Omodei U, Bonanni B.Source Cancer Prevention and Genetics, European Institute of Oncology, 20141 Milan, Italy.

Abstract BACKGROUND:We have previously reported the favourable effect of transdermal estradiol (E2), relative to oral conjugated equine oestrogen (CEE), on ultrasensitive C-reactive protein after 12 months of treatment in a retinoid-placebo controlled two-by-two randomized breast cancer prevention trial (Decensi A et al (2002) Circulation106 10 1224-8). Here, we investigate the changes in lipids and clotting profile in patients of the same trial.

METHODS AND RESULTS: Recent post-menopausal women were randomised to either oral CEE 0.625 mg/day and placebo (n = 55), CEE and fenretinide 200 mg/day (n = 56), transdermal E2 50 mg/day and placebo (n = 59) or E2 and fenretinide 200 mg/day (n = 56). Sequential medroxyprogesterone acetate 10 mg/day was given in each group.

After 12 months, there was a statistically significant effect of the route of administration of hormone replacement therapy (HRT) on fibrinogen levels; the median percentage change being -5.7% with CEE and -1.1% with E2 (p = 0.012).

Total cholesterol decreased in all arms (p < 0.0001). HDL-C decreased significantly with transdermal E2 (p = 0.006) compared to oral CEE and with fenretinide relative to placebo (p<0.001). Triglycerides exhibited an opposite modulation in the HRT route, with a 21.4% median increase with oral CEE and an 8.6% reduction with transdermal E2 (p < 0.0001). Antithrombin-III showed a 4% borderline significant reduction in the fenretinide arm relative to placebo, irrespective of the HRT administration route (p = 0.055).

CONCLUSIONS: Our data indicate that transdermal E2 may be preferable to oral CEE based on its safer cardiovascular risk profile. Fenretinide modified some cardiovascular risk biomarkers and confirmed a safer profile compared to other retinoids.

5) http://www.ncbi.nlm.nih.gov/pubmed/11341495

Thromb Haemost. 2001 Apr;85(4):619-25.

Effects of oral and transdermal estrogen replacement therapy on markers of coagulation, fibrinolysis, inflammation and serum lipids and lipoproteins in postmenopausal women. Vehkavaara S, Silveira A, Hakala-Ala-Pietilä T, Virkamäki A, Hovatta O, Hamsten A, Taskinen MR, Yki-Järvinen H.

Department of Medicine, University of Helsinki, Finland.Abstract
We compared the effects of oral estradiol (2 mg), transdermal estradiol (50 microg), and placebo on measures of coagulation, fibrinolysis, inflammation and serum lipids and lipoproteins in 27 postmenopausal women at baseline and after 2 and 12 weeks of treatment. Oral and transdermal estradiol induced similar increases in serum free estradiol concentrations.

Oral therapy increased the plasma concentrations of factor VII antigen (FVIIag) and activated factor VII (FVIIa), and the plasma concentration of the prothrombin activation marker prothrombin fragment 1+2 (F1+2).

Oral but not transdermal estradiol therapy significantly lowered plasma plasminogen activator inhibitor-1 (PAI-1) antigen and tissue-type plasminogen activator (tPA) antigen concentrations and PAI-1 activity, and increased D-dimer concentrations, suggesting increased fibrinolysis.

The concentration of soluble E-selectin decreased and serum C-reactive protein (CRP) increased significantly in the oral but not in the transdermal or placebo groups. In the oral but not in the transdermal or placebo estradiol groups low-density-lipoprotein (LDL) cholesterol, apolipoprotein B and lipoprotein (a) concentrations decreased while high-density-lipoprotein (HDL) cholesterol, apolipoprotein AI and apolipoprotein All concentrations increased significantly. LDL particle size remained unchanged.

In summary, oral estradiol increased markers of fibrinolytic activity, decreased serum soluble E-selectin levels and induced potentially antiatherogenic changes in lipids and lipoproteins. In contrast to these beneficial effects, oral estradiol changed markers of coagulation towards hypercoagulability, and increased serum CRP concentrations.Transdermal estradiol or placebo had no effects on any of these parameters.

6) http://www.ncbi.nlm.nih.gov/pubmed/16412400
Cardiovasc Res. 2006 Apr 1;70(1):22-30. Epub 2006 Jan 17.
Controversies regarding hormone therapy: Insights from inflammation and hemostasis.  Koh KK, Yoon BK.  Source  Vascular Medicine and Atherosclerosis Unit, Division of Cardiology, Gil Medical Center, Gachon Medical School, Incheon, Korea.
Abstract  Many observational studies and experimental and animal studies have demonstrated that estrogen therapy (ET) or hormone therapy (HT) significantly reduces the risk of coronary heart disease. Nonetheless, recent randomized controlled trials and the Nurses’ Health Study in secondary prevention demonstrate trends toward an increased risk of cardiovascular events rather than a reduction of risk from HT. HT has both anti-inflammatory and pro-inflammatory effects, and it activates coagulation and improves fibrinolysis. These effects depend on the route of administration, doses of estrogen, age of women, and the presence of coronary artery disease or the coexistence of other risk factors for hypercoagulability. In this review, we discuss effects of HT on markers of inflammation, hemostasis, and fibrinolysis that may link endothelial dysfunction in cardiovascular diseases. We also briefly discuss effects of lower doses of HT and tibolone in postmenopausal women.

7) http://www.ncbi.nlm.nih.gov/pubmed/11372667
Thromb Haemost. 2001 May;85(5):775-81.
The effects of hormone replacement therapy (HRT) on hemostatic variables in women with previous venous thromboembolism–results from a randomized, double-blind, clinical trial.  Høibraaten E, Qvigstad E, Andersen TO, Mowinckel MC, Sandset PM.  Source  Department of Hematology, Ullevål University Hospital, Oslo, Norway.In a recent randomized, double-blind, placebo-controlled trial of women with a history of venous thromboembolism (VTE), we found that hormone replacement therapy (HRT) was associated with an early excess risk of recurrent thrombosis. The aims of the present study were to characterize the effects of HRT on coagulation in these women to elucidate the mechanism(s) by which HRT increases the risk of thrombosis. The study comprised 140 women who were randomized to receive continuous treatment for 24 months with once daily 2 mg 17-beta-estradiol plus 1 mg norethisterone acetate (n = 71) or placebo (n = 69).

HRT caused significant increases in prothrombin fragments 1+2, thrombin-antithrombin complex, and D-Dimer after 3 months, but these changes were less pronounced on prolonged treatment. The increases in markers of activated coagulation was higher in those women who subsequently developed recurrent thrombosis, but was similar in carriers and non-carriers of the factor V Leiden mutation. HRT had no effects on fibrinogen and factor VIII. Activated factor VII, but not factor VII antigen, decreased significantly on HRT as compared with placebo. The coagulation inhibitors antithrombin, protein C, and TFPI, but not protein S, all showed significant sustained decreases in the HRT group as compared with placebo. Antithrombin and protein C decreased by 8-12% on HRT, whereas TFPI activity decreased by 12-17% and TFPI free antigen by 29-30%. In multivariate analysis, only TFPI activity was a significant predictor for the increased activation of coagulation. We conclude that HRT was associated with early activation of coagulation, which corroborates the finding of an early risk of recurrent VTE. This activation may in part be explained by reduction in circulating anticoagulants.

Images:

http://commons.wikimedia.org/wiki/File:Estrogen_patch.jpg

http://tuesdayshorse.files.wordpress.com/2010/10/expandable_poster.png

http://www.horsefund.org/pmu-faq.php

The Safety of Bio-Identical Hormones by Jeffrey Dach MD

The Safety of Bio-Identical Hormones by Jeffrey Dach MD

Are Women’s Bio-identical hormones Safe?

Bio-identical hormones exist naturally in the human body, so it is axiomatic that these are safe.  However, we are interested in a slightly different question. What is the safety of bio-identical hormones as routinely used in medical practice?  Let’s try to answer this question. 

The Safety of Water compared to Bio-Identical Hormones

  Water is safe, beneficial and healthy.  Yet, even so, drinking excess amounts of water causes death from Fatal Water Intoxication.(1)
Left Image: Water with Droplets Courtesy of Wikimedia
Similarly, just like water, bio-identical hormones are safe and beneficial when used at proper dosages.  Like excessive water, excessive hormone dosage may result in their own adverse side effects.  Excess estrogen, for example, causes fluid retention, breast sensitivity and enlargement, and disturbed mood.

Humans Have Bio-Identical Hormones.

Another answer to the safety question is that bio-identical hormones are found in the human body naturally.  Any harmful substance in the human body would impair survival, and over millions of years of evolution would be eliminated by natural selection.  This is the basic concept of Darwinian evolution which is accepted by mainstream medical science.

A 50 Million Year Medical Experiment

Consider the following medical experiment, performed over the last 50 million years with the help of our friend, Darwinian evolution.(2)  Bio-Identical Hormones have been present in the human body for 50 million years, and we humans are still here on the planet.  I would consider that a successful medical experiment, wouldn’t you?

Either Excess or Deficiency of Anything Can be Harmful

One of our routine labs tests called the Chem Panel measures electrolytes and glucose levels in the blood. The body automatically maintains these within narrow ranges to maintain health.  If levels deviate above or below these normal ranges, this causes a serious health disturbance.  For example elevated potassium levels causes cardiac arrest.  Magnesium deficiency causes muscle spasm and arrythmia. Excessive amounts of Vitamins A and D are toxic.  Hormones levels enjoy a considerably wide range of acceptable limits.  Even so, a deficiency or an excess of women’s bio-identical hormones can produce adverse symptoms.  This is called estrogen deficiency/excess, and progesterone deficiency/excess, and they each have typical signs and symptoms easily recognized.(3)
 
Common Signs of Estrogen Deficiency (4)

Mental fogginess
Forgetfulness
Depression
Minor anxiety
Mood change
Difficulty falling asleep
Hot flashes
Night sweats
Temperature swings
Day-long fatigue
Reduced stamina
Decreased sense of sexuality
Lessened self-image and attention to appearance
Dry eyes, skin, and vagina
Loss of skin radiance
Feel balanced 2nd part of cycle
Sagging breasts and loss of fullness
Pain with sexual activity
Weight gain
Increased back and joint pain
Episodes of rapid heartbeat
Headaches and migraines
Gastrointestinal discomfort
Constipation

Common Signs of Excess Estrogen (takes longer to notice)

Breast tenderness or pain
Increased breast size
Water retention, fingers, legs
Impatient, snappy behavior, but with clear mind
Pelvic cramps
Nausea
Common Signs of Progesterone Deficiency
No period at all (no ovulation)
The period comes infrequently (every few months)
Heavy and frequent periods (large clots, due to buildup in the uterus)
Spotting a few days before the period. (Progesterone level is dropping)
PMS
Cystic breasts
Painful breasts
Breasts with lumps
Most cases of endometriosis, adenomyosis, and fibroids.
Anxiety, irritability, nervousness and water retention
Above list courtesy of Uzzi Reiss MD OB GYN. (4)

No Reported Adverse Events from Bio-Identical Hormones

Over-the-counter pain pills (NSAIDs) such as aspirin, naproxen and ibuprofen are considered fairly safe.  After all, you don’t need a prescription to buy them, yet they cause an estimated 16,500 deaths in the US annually, mostly from gastric bleeding.(5)  Compare this to no reported adverse events from bio-identical hormones last year, according to an FDA press conference January 2008.(6)

Do Bio-Identical Hormones Cause Breast Cancer?(7)

The answer is NO.

According to the French Cohort study, there is no increase in breast cancer in women using bio-identical hormones.(8)  However, having said that, avoiding excess environmental estrogens as well as excessive estrogen levels from any source, is the key to preventing breast cancer.(9)  My previous article covers our program for breast cancer prevention which includes iodine supplementation, Indole-3-carbinol and fiber. To read about this, see: Breast Cancer Prevention and Iodine Supplementation by Jeffrey Dach MD.(10)
Left Image: Eiffel Tower Paris France Courtesy of Wikimedia Commons

Do Bio-Identical Hormones Cause Heart Disease ?

Again, the answer is NO. A study of CAT calcium scores by JoAnn E. Manson in the June 2007 JAMA actually showed less heart disease in the women taking unopposed estrogen (they had hysterectomies and were not given the synthetic progestins).(11)  These same results had already been published 2 years previously in a calcium score study by Budoff in J Womens Health 2005. (12)

A Closer Look at the Women’s Health Initiative WHI Study

Understanding the Women’s Health Inititative (WHI) study is not difficult, and is very important to answer the question of hormone safety.  The WHI study was the large NIH sponsored medical study which compared synthetic hormones to placebo in two large groups of women.  The WHI study consisted of two arms.  The first arm used the synthetic hormones Premarin and Provera,  and the second arm used Premarin alone.(13)(14)

What is Premarin and Provera?

Premarin and Provera are not bio-identical hormones.  Premarin is a hormone obtained from pregnant horses, which contains Equilin, a horse hormone not found in humans.(15)  Provera is a synthetic hormone which is not found anywhere in the natural world (see provera diagram below).(16)   The Premarin and Provera combination is called PremPro, a synthetic hormone pill commonly prescribed by mainstream medicine.  Prempro was the hormone preparation used in the first arm of the WHI study.(13)

WHI study First Arm:

The WHI study (first arm published in JAMA 2002) was terminated early because the combination of premarin and provera (Prempro) caused increased breast cancer and heart disease.(13)Immediately after this study was published, there was a massive switch by women to bio-identical hormones which resulted in a 4 billion dollar loss for Wyeth, the maker of Prempro.  Wyeth is still trying to recoup that money by manipulating the FDA.  They want the FDA to ban their competition, the bio-identical hormones or their components.(36)(37)(38)  Use this easy tool to email your Congressman and voice your opposition to Wyeth’s attempts to ban estriol and other bio-identical hormones.(17)  While you are at it, tell your Congressman that synthetic hormones are chemically altered monsters that should be banned.

WHI Study (Second Arm):

All the women in the second arm of the WHI study had prior hysterectomies (uterus absent), so they did not need the synthetic progestin, provera commonly given to  prevent endometrial cancer.   Rather, they were only given Premarin (the horse hormone, also called CEE, for Conjugated Equine Estrogen).  Unlike the first arm of the study, these women had no increase in breast cancer risk.(18) (see chart below)

WHI second arm jeffrey dach md

Above Left Chart: This chart shows data from the  second arm of the WHI in JAMA 2004.(14)

The blue bars represents adverse events in the placebo group. The red bars represents adverse events in women (ages 50-59) on premarin only, with no Provera (progestin).  Note that the Red bars are all Lower than the Blue bars. The Red bar (Premarin-only) group shows LESS heart disease, LESS breast cancer and LESS Mortality when compared to placebo (blue bar).  Chart Courtesy of Susan Ott MD Bone Physiology.(19)

Premarin causes endometrial cancer, so the mainstream medical system always gives Provera (progestins) to prevent endometrial cancer, unless of course, the uterus is absent from prior hysterectomy.(20)

The WHI Culprit was the Synthetic Progestin (an altered form of Progesterone)

Back to the first arm of the WHI which used Prempro, it is clear from the data that the  culprit which caused breast cancer and heart disease was Provera, a synthetic monster hormone.  This is nothing new.  For years, Provera has been known to cause heart disease  and breast cancer.(21)(22)(39)

Provera Proven to Cause Breast Cancer

In fact, medical studies prove that Provera causes breast cancer.  In these studies, Primates were treated with either Progesterone or Provera showing that the Provera causes breast cancer, while the Progesterone provides protection from breast cancer.(22)

Monster Hormones are Chemically Altered

Chemically altered hormones were used in the WHI study, and are routinely handed out by the medical system.  These altered hormones are monsters that should never have been approved for marketing to the American people.  They should be banned.



The Media Says Hormones Cause Cancer and Heart Disease

If bio-identical hormones are so safe, then why do the newspapers say that women’s hormones cause breast cancer and heart disease?(23)

The answer is that the media and the medical profession routinely confuse synthetic chemically altered monster hormones with the bio-identical hormones.  The drug companies intentionally create this confusion because they want to hide the fact that synthetic hormones are monsters that should be banned.
Chemically altered hormones were made because of a quirk in our legal system which grants patent protection for chemically altered versions of a natural substance.  The natural hormones were chemically altered so that they could be patented to protect profits from competition.  Naturally occurring bio-identical hormones by law cannot be patented.

Examples of monster synthetic hormones are provera, all progestins, and birth control pills which are never found in nature. These are the monster hormones.

A Listing of a Few Monster Hormones:

Chemically Altered forms of progesterone:
Dienogest, Desogestrel, Drospirenone, Dydrogesterone, Ethisterone, Etonogestrel, Ethynodiol diacetate, Gestodene, Gestonorone, Levonorgestrel, Lynestrenol, Medroxyprogesterone, Megestrol, Norelgestromin, Norethisterone, Norethynodrel, Norgestimate, Norgestrel, Norgestrienone, Tibolone
Chemically altered forms of estrogen:
Dienestrol, Diethylstilbestrol, Ethinylestradiol, Fosfestrol, Mestranol
Chemically alered hormones in BCP’s Birth Control Pills:
levonorgestrel and ethinyl estradiol [oral contraceptive] (ALESSE 28, AVIANE, NORDETTE, SEASONALE, TRIPHASIL, TRIVORA-28); norethindrone and ethinyl estradiol (COMBI PATCH, LOESTRIN FE 1/20, NEOCON 1/35, ORTHO-NOVUM 7/7/7, OVCON 35); norgestimate and ethinyl estradiol (ORTHO-CYCLEN, ORTHOTRI-CYCLEN, TRINESSA); norgestrel and ethinyl estradiol (LO/OVRAL 28, LOW-OGESTREL), desogestrel and ethinyl estradiol (DESOGEN, MIRCETTE, ORTHO-CEPT), drospirenone and ethinyl estradiol (YASMIN)
Chemically altered forms of testosterone:
Androstanolone, Fluoxymesterone, Mesterolone, Methyltestosterone
How to make a Monster Hormone, Add a Side-Chain (in Red below)
Below Images: Courtesy of wikimedia commons.
  
Human  Progesterone                   Provera – the Monster Hormone

Take a good look at human bio-identical Progesterone (Upper left), and the chemically altered version (upper right) Provera (medroxyprogesterone).  The added side-chain is labeled in RED on the right side of the Provera molecule.  This side-chain (in red) has been added in order to make a totally new structure that can be patented, and is the only difference with progesterone (upper left).  In the process of adding this side-chain, a Monster was created.  In the opinion of John R Lee MD,  “to prescribe a chemically altered version of progesterone called Provera is medical malpractice”, and yet this practice is common in mainstream medicine.

An Illustration which Explains the Problem with Synthetic Chemically Altered Drugs

Supposing a biochemist working for a drug company has an idea to alter the chemical structure of vitamin C so a patent can be obtained.  The biochemist adds a chlorine molecule to the vitamin C carbon ring, and gives is a new name “super-Vitamin C”, which is really a chlorinated version of vitamin C.  Next they do a one year medical study with 5,000 people taking the chlorinated vitamin C tablet every day, and another 5000 people taking a placebo.  After the year is up, they count a .5 per cent incidence of heart disease events in the Super Vitamin C group and a 1.0 percent in the placebo group.   FDA approval is easily obtained based on  reduction in heart disease events by 50 per cent (.5 per cent is 50% of 1.0 %).  The drug company is at liberty to spend million dollars on television advertising designed to rake in millions more for the new heart prevention miracle drug.  This absurd scenario is now the norm for our medical system.  Why would anyone want to spend money for a monster version of vitamin C when the real thing is available for pennies?  Why use a monster hormone when human hormones  are available?  Compared to their monster counterparts, Bio-Identical Hormones are more effective, have fewer adverse side effects, and are less costly.

High Hormone Levels of Early Pregnancy Confer Protection from Breast Cancer.

During the 16th century in Italy, breast cancer was quite rare.  An Italian doctor, Bernardino Ramazzini, noted in 1713 the relatively high incidence of breast cancer in nuns and wondered whether this was related to celibate lifestyle.(24)  Recent studies confirm that early pregnancy and multiple pregnancies confer protection from breast cancer, while no pregnancies (as in the nuns) leads to increased risk of breast cancer.(25)  This protection is thought to be confered by high levels of progesterone.  This was confirmed in a 2007 study by Rajkumar who showed that hormone treatment protected genetically engineered mice from developing breast cancer. (26)

Left image Pregnancy, courtesy of wikipemedia commons.

Progesterone, the Great Protector

Progesterone is so safe, it is available over the counter without a prescription.  In addition, a deficiency of progesterone is associated with an increase in breast cancer risk.(27)  Progesterone is known to be protective and prevents breast cancer.(28)

Why Don’t Birth Control Pills use Natural Progesterone?

Birth Control Pills, BCP’s, are very effective at preventing pregnancy by suppressing ovulation. However, BCP’s contain synthetic hormones which have adverse side effects.(29)(30)(31)  To avoid these monster hormones,  the IUD (intra-uterine device) is available.
Here is a listing of people involved in the early  development of birth control pills: Russell Marker, Percy Lavon Julian, Carl Djerassi, Luis E. Miramontes, George Rosenkranz, Gregory Pincus, Min Chueh Chang, John Rock.(32)

In the future of medicine, I predict that progesterone will replace progestins as oral contraception .  The bio-identical hormone, Progesterone, will be used in the birth control pills of the future.  Early research on contraception was done with progestereone, and research was switched to synthetic progestins to obtain a patent and make a profit. Another consideration was ease of use of the oral tablet, at the time available only as a progestin.  Bio-Identical progesterone suppresses ovulation and was the original agent investigated in early research for a contraceptive agent.  However, timing and dosages were never officially worked out, so we currently are left with the synthetic birth control  pills by default.  Again, the IUD can be used instead to avoid the monster hormones.   I predict that new research outside the US in the next decade will establish progesterone as the hormone of choice for birth control.  Most likely, funding for this research will come from a foreign government agency, in a country with universal health care which has economic incentives to make a healthier pill.

More on Breast Cancer and Hormone Levels

If high estrogen levels were the primary cause of breast cancer, we would expect to find more breast cancer mortality in women with higher hormone levels at age 30, and less breast cancer in women with low hormone levels at age 60 (post-menopausal).  However, what we find is the exact opposite.  According to the CDC, mortality from breast cancer is 7 times higher in the older women aged 60 (0.7 per cent), compared to younger women aged 30 (0.1 per cent).  Mortality from breast cancer is 700 % higher in post-menopausal women with low hormone levels.(link)

Conclusion

In conclusion, bio-identical hormones used at appropriate dosages are safe, effective, and beneficial for health.  On the other hand, any chemical alteration of a human hormone creates a monster hormone, which is not bioidentical.  These monster hormones should never have been approved for marketing and sale to the American people.  These monster hormones are unsafe, causing cancer and heart disease, and should be banned immediately.

Read more on this topic at

The Importance of BioIdentical Hormones by Jeffrey Dach MD .

Three Excellent Articles on the Safety of BioIdentical Hormones

(1) For a good summary and explanation of the issues, I recommend the article, The Case for Bioidentical Hormones  Steven F Hotze MD. 2008.(33)
(2) Another excellent article is The Safety of Bioidentical Hormones — the Data vs. the Hype by Jacob Teitelbaum, MD From the Townsend Letter June 2007.(34)
(3) A third excellent article: Bioidentical vs. Synthetic HRT, A Review of the Literature
by the Bio-Identical Hormone Inititiative, Erika Schwartz MD, David Brownstein MD, Kent Holtorf MD.(40)(41)
Recommended Reading: books by John R Lee MD (35)
WHAT YOUR DOCTOR MAY NOT TELL YOU ABOUT MENOPAUSE: The Breakthrough Book on Natural Progesterone (Warner Books, 1996)(35)
WHAT YOUR DOCTOR MAY NOT TELL YOU ABOUT PREMENOPAUSE: Balance Your Hormones and Your Life from Thirty to Fifty (Warner Books, 1999)(35)
WHAT YOUR DOCTOR MAY NOT TELL YOU ABOUT BREAST CANCER: How Hormone Balance Can Help Save Your Life, (Warner Books, 2002)(35)

Jeffrey Dach MD
www.jeffreydach.com
www.naturalmedicine101.com
www.truemedmd.com

References
(1)  http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=1770067
Fatal water intoxication. D J Farrell1 and L Bower. J Clin Pathol. 2003 October; 56(10): 803–804.
(2) http://en.wikipedia.org/wiki/Charles_Darwin
Charles Darwin, theory of natural selection.
(3)
http://www.johnleemd.com/store/premenstrual_syndrome.html
Excerpted From: WHAT YOUR DOCTOR MAY NOT TELL YOU ABOUT BREAST CANCER:
Balance Your Hormones and Your Life from Thirty to Fifty. PHYSIOLOGICAL EFFECTS OF ESTROGEN AND PROGESTERONE. How Hormone Balance Can Help Save Your Life. by John R. Lee, M.D., David Zava, Ph.D. and Virginia Hopkins. Warner Books 2002
(4) http://www.uzzireissmd.com/book_naturalhormone.html
Natural Hormone Balance for Women: Look Younger, Feel Stronger, and Live Life with Exuberance. by Uzzi Reiss MD
(5) http://www.drtheo.com/news/NSAIDs.pdf
Medical Progress. p 1888. June 17, 1999 The New England Journal of Medicine
GASTROINTESTINAL TOXICITY OF NONSTEROIDAL ANTIINFLAMMATORY DRUGS M. MICHAEL WOLFE , M.D., DAVID R. LICHTENSTEIN, M.D.,AND GURKIRPAL SINGH, M.D.
(6) http://www.fda.gov/bbs/transcripts/transcript010908.pdf
Transcript of FDA Press Conference on FDA Actions on Bio-Identical Hormones
FTS HHS FDA Susan Cruzan January 9, 2008
(7) http://www.womentowomen.com/breasthealth/estrogenbreastcancer.aspx
Causes of Brea6t Cancer- the Estrogen Controversy, Dixie Mills MD
(8) http://www.ncbi.nlm.nih.gov/pubmed/12626212
Climacteric. 2002 Dec;5(4):332-40. Combined hormone replacement therapy and risk of breast cancer in a French cohort study of 3175 women.de Lignières B et al.
French Cohort Study.
(9) http://www.johnleemd.com/store/cancer_progest.html
Breast Cancer Book Intro. WHAT YOUR DOCTOR MAY NOT TELL YOU ABOUT BREAST CANCER. How Hormone Balance Can Help Save Your Life
By John R. Lee, M.D., David Zava Ph.D., and Virginia Hopkins INTRODUCTION
(10)
http://jeffreydach.com/2007/05/05/jeffreydachdrdachiodine.aspx
Breast Cancer Prevention and Iodine Supplementation by Jeffrey Dach MD
(11) http://content.nejm.org/cgi/content/short/356/25/2591
Estrogen Therapy and Coronary-Artery Calcification. NEJM Volume 356:2591-2602  June 21, 2007  Number 25. JoAnn E. Manson, M.D., et al.
(12) http://www.ncbi.nlm.nih.gov/pubmed/15989413
J Womens Health (Larchmt). 2005 Jun;14(5):410-7. Effects of hormone replacement on progression of coronary calcium as measured by electron beam tomography.Budoff MJ, et al.
(13) http://jama.ama-assn.org/cgi/content/abstract/288/3/321
Risks and Benefits of Estrogen Plus Progestin in Healthy Postmenopausal Women
Principal Results From the Women’s Health Initiative Randomized Controlled Trial
Writing Group for the Women’s Health Initiative Investigators JAMA. 2002;288:321-333. First Arm.
(14) http://jama.ama-assn.org/cgi/content/full/291/14/1701
Effects of Conjugated Equine Estrogen in Postmenopausal Women With Hysterectomy
The Women’s Health Initiative Randomized Controlled Trial.  JAMA. 2004;291:1701-1712. Second Arm. This is the Second Arm of the Study. Premarin Only.
(15) http://en.wikipedia.org/wiki/Premarin
Premarin From Wikipedia, the free encyclopedia
(16) http://en.wikipedia.org/wiki/Medroxyprogesterone
Provera, Medroxyprogesterone, From Wikipedia, the free encyclopedia
(17) http://homecoalition.org/TakeAction
Take Action. Write a letter to your elected officials using our online advocacy tool.
Act now to defend your right to bio-identical hormones! Please contact your
congressional representative, senators, and the White House immediately.
HOMECoalition.org.
(18) http://jama.ama-assn.org/cgi/content/full/295/14/1647
Effects of Conjugated Equine Estrogens on Breast Cancer and Mammography Screening in Postmenopausal Women With Hysterectomy. Marcia L. Stefanick, PhD et al. for the WHI Investigators. JAMA. 2006;295:1647-1657. Conclusions  Treatment with CEE alone for 7.1 years does not increase breast cancer incidence in postmenopausal women with prior hysterectomy.
(19)
http://courses.washington.edu/bonephys/opestrogen.html#WHI
Osteoporosis and Bone Physiology, Susan Ott, MD, Associate Professor, Department of Medicine, University of Washington.  A Review of the results from the Women’s Health Initiative.
(20) http://www.ncbi.nlm.nih.gov/pubmed/3358913
The dose-effect relationship between ‘unopposed’ oestrogens and endometrial mitotic rate: its central role in explaining and predicting endometrial cancer risk.Key TJ, Pike MC.
Br J Cancer. 1988 Feb;57(2):205-12.
(21) http://atvb.ahajournals.org/cgi/content/full/24/7/1171
Should Progestins Be Blamed for the Failure of Hormone Replacement Therapy to Reduce Cardiovascular Events in Randomized Controlled Trials?
Kwang Kon Koh; Ichiro Sakuma. Arteriosclerosis, Thrombosis, and Vascular Biology. 2004;24:1171.
(22) http://www.ncbi.nlm.nih.gov/pubmed/16841178
Effects of estradiol with micronized progesterone or medroxyprogesterone acetate on risk markers for breast cancer in postmenopausal monkeys.Wood CE et al. Breast Cancer Res Treat. 2007 Jan;101(2):125-34.
(23) http://www.time.com/time/magazine/article/0,9171,1002897,00.html
The Truth About Hormones Monday, Jul. 22, 2002 Time Magazine. By CHRISTINE GORMAN AND ALICE PARK
(24) http://www.ama-assn.org/amednews/2006/04/17/hlsa0417.htm
AMA Medical NEws. Collecting clues: Cancer registries might have an answer. By Kathleen Phalen Tomaselli, AMNews correspondent. April 17, 2006.
(25) http://breast-cancer-research.com/content/7/3/131
The protective role of pregnancy in breast cancer. Jose Russo et al.Breast Cancer Research 2005, 7:131-142doi:10.1186/bcr1029
(26) http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=17257424
Hormone-induced protection of mammary tumorigenesis in genetically engineered mouse models
Lakshmanaswamy Rajkumar et al.Breast Cancer Res. 2007; 9(1): R12.
(27) http://aje.oxfordjournals.org/cgi/content/abstract/114/2/209
BREAST CANCER INCIDENCE IN WOMEN WITH A HISTORY OF PROGESTERONE DEFICIENCY
LINDA D. COWAN et al. American Journal of Epidemiology Vol. 114, No. 2: 209-217
(28) http://www.annclinlabsci.org/cgi/content/abstract/28/6/360
Progesterone inhibits growth and induces apoptosis in breast cancer cells: inverse effects on Bcl-2 and p53.  B Formby and TS Wiley. Annals of Clinical and Laboratory Science, Vol 28, Issue 6, 360-369
(29) http://en.wikipedia.org/wiki/Birth_control_pill
Combined oral contraceptive pill. From Wikipedia, the free encyclopedia. (Redirected from Birth control pill)
(30) http://www.worstpills.org/results.cfm?disease_id=26
Oral Contraceptives on Worst Pills.org. The pill can cause many adverse effects. Some of them are merely a nuisance, while others can be life-threatening. The pill can cause headaches, bloating, nausea, irregular bleeding and spotting, breast tenderness, weight gain, or vision changes. Other more serious adverse effects that can occur from a few months to a few years after starting oral contraceptives include high blood pressure, gallbladder disease, liver tumors, depression, and metabolic disorders, such as diabetes. Temporary infertility has been associated with the period of time right after pill use is stopped. But the two most dangerous risks associated with taking birth control pills are blood clots and cancer.
(31)
http://www.jeffreywarber.com/hc%20pages/pillsideeffects.html
Birth COntrol Pill Adverse Side Effects by Jeffrey Warber MD
(32) http://www.quickoverview.com/reproductive/birth-control-pill.html
History and Development of an effective combined oral contraceptive. People Involved.
(33) http://www.jpands.org/vol13no2/hotze.pdf
Point/Counterpoint: The Case for Bioidentical Hormones Steven F. Hotze, M.D.Donald P. Ellsworth, M.D.Journal of American Physicians and Surgeons Volume 13 Number 2 Summer 2008
(34)
http://www.townsendletter.com/June2007/painfree0607.htm
The Safety of Bioidentical Hormones — the Data vs. the Hype by Jacob Teitelbaum, MD
(35) http://www.johnleemd.com/store/main_books.html
Books by John R Lee MD
Wyeth and the FDA

(36)   http//:naturalnews.com/022595.html
FDA’s Assault of Bioidentical Hormones Demonstrates Pro-Pharma Loyalties, Disregard for Consumer Choice Tuesday, February 05, 2008 by: Mike Adams
(37)  http://www.drerika.com/blog?action=viewBlog&blogID=-751271156172620113
February 16, 2008. Women, Doctors Wage Crucial Battle With FDA To Save Bioidentical Hormones From Wyeth’s Wrath. A major coalition of informed women and their doctors have launched an all out war on the Federal Drug Administration’s (FDA) cynical and corrupt decision to ban compounded hormones containing Estriol.
(38) http://jeffreydach.com/2008/01/11/fda-declares-war-on-bioidentical-hormones-by-jeffrey-dach-md.aspx
FDA Declares War on BioIdentical Hormones by Jeffrey Dach MD
Provera and Heart Disease
(39) http://atvb.ahajournals.org/cgi/content/full/17/1/217
Medroxyprogesterone Acetate Antagonizes Inhibitory Effects of Conjugated Equine Estrogens on Coronary Artery Atherosclerosis. Michael R. Adams; Thomas C. Register; Deborah L. Golden; Janice D. Wagner; J. Koudy Williams .Arteriosclerosis, Thrombosis, and Vascular Biology. 1997;17:217-221.
Bio-Identical Hormone Inititiative
(40)
http://www.drerika.com/pg/jsp/bhi/bioidentical_vs_synthetic.pdf
Bioidentical vs. Synthetic HRT, A review of the literature
(41) http://www.bioidenticalhormoneinitiative.org/
Bio-Identical Hormone Inititiative, Erika Schwartz MD, David Brownstein MD, Kent Holtorf MD
Additional References
http://www.endfatigue.com/health_articles_f-n/Menapause-safety_effectiveness_bioidentical_hormones.html
The Safety and Effectiveness of Bio-Identical Hormones: Natural (Bio-Identical) vs. Synthetic HRT
Kent Holtorf, M.D. Dr. Holtorf is the Medical Director of the Holtorf Medical Group, Inc, Center for Hormone Imbalance and Fatiguing Conditions in Los Angeles, specializing in CFS, FM, hypothyroidism, chronic illness and the treatment of complex endocrine dysfunction. He is board certified and is a Board Examiner for the American Academy of Anti-Aging Medicine. He is also chief of the Medical Advisory Board for the Fibromyalgia and Fatigue Centers, Inc.
http://www.thorne.com/media/hormones11-3.pdf
A Comprehensive Review of the Safety and Efficacy of Bioidentical Hormones for the Management of Menopause and Related Health Risks Deborah Moskowitz, ND.  Altern Med Rev 2006;11(3):208-223)
http://www.drcranton.com/hrt/hrt_references.htm
Hormone Replacement References.  Most references below are linked to the National Library of Medicine (MEDLINE)
http://www.medscape.com/viewarticle/408096_print
Special Article: Addressing Postmenopausal Estrogen Deficiency: A Position Paper of the American Council on Science and Health January 26, 2001 Sander Shapiro, MD Medscape General Medicine 3(1), 2001.
http://www.drerika.com/pg/jsp/general/scientificarchive.jsp
Scientific Literature on Hormones on Dr Erika.com
http://www.womeninbalance.org/research/
research available women in balance.
Fatal Water Intoxication
http://www.msnbc.msn.com/id/16614865/
Woman dies after water-drinking contest
Natural and Synthetic Substances in Medicine
http://www.fimdefelice.org/archives/arc.promise.html
The Promise and Problems of Natural Substances in Medicine Stephen L. DeFelice, M.D.
http://www.iupac.org/publications/pac/2002/pdf/7410×1957.pdf
Natural and synthetic substances related to human health. The dubious honor of being the most powerful toxic substance goes to a protein produced by the bacterium, Clostridium botulinum. This protein is responsible for fatal food poisoning—botulism—being produced when the bacterium grows in the absence of oxygen in canned or preserved food. 2002 IUPAC, Pure and Applied Chemistry 74, 1957–1985
Synthetic Hormones and Breast Cancer
http://www.nwhn.org/healthinfo/detail.cfm?info_id=9&topic=Fact%20Sheets
Menopause Hormone Therapy and Breast Cancer. National Women’s Health Network
http://www.bmj.com/cgi/content/full/310/6979/598/b
BMJ 1995;310:598 (4 March) Letters Risk factors for breast cancer
Hormone Levels, Age and Breast Cancer
http://www.cdc.gov/cancer/breast/statistics/age.htm
Risk of Breast Cancer by Age, CDC .Percent of U.S. Women Who Die from Breast Cancer Over 10-, 20-, and 30-Year Intervals. According to Their Current Age, 2002–2004. Age 30 is 0.1%  age 60 is 0.7% .
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The reader is advised to discuss the comments on these pages with his/her personal physicians and to only act upon the advice of his/her personal physician. Also note that concerning an answer which appears as an electronically posted question, I am NOT creating a physician — patient relationship. Although identities will remain confidential as much as possible, as I can not control the media, I can not take responsibility for any breaches of confidentiality that may occur.

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