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Natural HRT Women, Benefits, bad pharma, and estrogens basics

2006, then 2 Major rewrites 2018 & 19  http://healthfully.org/rc/id2.html  3/23/2020 

 

HRT: The lack of sex hormones is the reason why women’s health declines precipitously after menopause and contributes to weight gain.  It is part of how the way nature cullies the elderly (BIOLOGICAL CLOCK). 

The long-term use of the best of the synthetic estrogen and a synthetic progesterone (called a progestin) has been shown to DECREASE the risk of:  Alzheimer’s 83%, Heart attacks 51%, Coronary Heart Disease 50%, Colorectal Cancer 46%, Breast Cancer 72%, Thrombosis 8%, Osteoporosis Fractures 90%, Macular degeneration 65%, reduces & prevents arthritic join destruction, firmer breasts, healthier skin (less wrinkles and thicker, 48% more collagen), reduces hair loss, increased libido & improves cognitive function, mental health, and extends life.. These claims are referenced below and at http://healthfully.org/fhr/.  The old results would have been better if the natural replacement hormones (NHRT) were used.  One major study of the literature looked at natural transdermal estradiol and progesterone.[1] Because natural HRT can’t be patented, a clinical trial hasn’t been funded, so the evidence is mainly based on functional differences between altered forms of the steroids and NHRT.  A very large body of research has been generated on the sex steroids, for which the article on transdermal application of progesterone and estradiol has over 200 citations.  But not being patented, there isn’t funds for a quality clinical trial.  The natural form of bioactive compounds is superior because evolution has evolved to maximize survival in the village during our paleo period.    



[1] The transdermal application is used to avoid metabolism by the liver on first pass following absorption by the intestines.  Metabolism averages around 95%, thus making oral usage ineffective, possible result in adverse consequences due to abnormal high levels of bioactive metabolites.   “The non-oral estrogen administration is largely devoid of such changes. . . .” at 2008.  



Section I:  The basics on sex Hormones (steroids):  [Mainly from Wikipedia articles, 2007]:  There are 3 classes sex hormone, estrogens, androgens, and progesterones.  “The polypeptide hormones luteinizing hormone, follicle-stimulating hormone and gonadotropin-releasing hormone are usually not regarded as sex hormones, although they play major sex-related roles” Wiki.  Estradiol is made by gonads, adrenal glands and in some other tissues such as the liver, fat, and glial cells of the brain where estradiol is an important neural steroid.  Estrogens are a group of related compounds named for their importance in the estrous cycle of humans and animals.  They are the primary female sex hormones.  Natural estrogens are steroid hormones, while some synthetic ones are non-steroidal.  The name comes from the Greek οἶστρος (oistros), literally meaning "gadfly" but figuratively sexual passion or desire, and the suffix -gen, meaning "producer of".  Estrogens are synthesized in all vertebrates as well as some insects thus having an ancient history.  Like all steroid hormones, estrogens readily diffuse across the cell membrane and some organelles such as the mitochondria.   Once inside the cell, they bind to and activate estrogen receptors which in turn modulate the expression of many genes.[4]  Additionally, estrogens have been shown to activate a G protein-coupled receptor, GPR30.  The four major naturally occurring estrogens in women are (E1) estrone, (E2) estradiol, (E3) estriol, and (E4) esterol.  Estradiol (E2) is the predominant estrogen during reproductive years both in terms of free serum levels as well as in terms of estrogenic activity. Estradiol is about 10 times as potent as estrone and about 80 times as potent as estriol in its estrogenic effects.  Estrone is secreted by the ovary, adipose [fat] tissue, and placenta.  E1 as sulfate it acts as a reservoir that can be converted as needed to estradiol.[1]  During menopause, estrone is the predominant circulating estrogen; while Estriol is during pregnancy in terms of serum levels.  Though estriol is the most plentiful of the three estrogens, it is also the weakest.  Estradiol is the most important estrogen in non-pregnant females who are between the menarche and menopause stages of life.   A 4th type of estrogen called estetrol (E4) is produced only during pregnancy.  All of the different forms of estrogen are synthesized from cholesterol which produces androgens, specifically testosterone and androstenedione, by the enzyme aromatase.  Follicle-stimulating hormone (FSH) stimulates the ovarian production of estrogens by the granulosa cells of the ovarian follicles and corporalutea.  Some estrogens are also produced in smaller amounts by the liver, [the brain & fat cells], adrenal glands, and the breasts.  Androstenedione has weak androgenic activity [muscle building] & is the predominant precursor for the more potent androgens such as testosterone as well as estrogen. Among estrogen’s over 2-dozen bodily functions.  E.g., their lowering the remodeling threshold prevents osteoporosis.  [Extensive oxidative damage and glycation by fructose affects the mitochondria and thus autophagy, and its ATP production, this is the primary causal factors for conditions associated with the western diet (once commonly called conditions of affluence).  The principle sex hormones reduce such damage.]  Estrogens are distributed in most tissues, especially the breast, uterine, vagina, and has a high affinity to adipose tissue., and is also maid by the glia cells in the brain.  Estrogens are metabolized in the liver and excreted as metabolites by the kidney.  Their levels are tightly controlled.  With receptors for estrogens in every cell and also in the mitochondria and the significant amount of the hormones circulating premenopausal it must be salubrious, and has functioned to make us healthy in the paleo state.[2]


All estrogens modulate the expression of many genes, with some such as GPER30 being only turned on by estradiol.  GPER30 has high expression in the pituitary gland, hypothalamus, adrenal medulla, kidney medulla, breast epithelial tissue, and developing follicles of the ovaries.[3]  Mainly estradiol affect the GPER transcription factors that turn on a number of genes of which affects lipo storage, bone remodeling, and glucose tolerance; and there are other affected transcription factors.  Given the complexity, without strong evidence it is safest to use the natural hormone in a tri-phasic formulation or simple lotion.  Taking NHRT will continue the health benefits associated with progesterone and & estradiol as one ages.  Estradiol and dehydroepiandrosterone (DHEA) another vital sex hormone during menopause and andropause sharply declines.  Women have about 1/10th the level of testosterone as men, obtain from conversion of estradiol which differs from testosterone by one functional group. As estradiol drops with menopause so too does testosterone to which about 10% of estradiol is converted to testosterone to maintain muscle mass.  A small amount of testosterone is good, and once widely used in HRT formulation popular in Europe.  The benefits of natural HRT are to slow the clock of aging.   The youthful estradiol level is > 300 pmol/L, or > 80 pg/mL.  Given lower bioactive with age, a higher level, probably double, is better.   Section three lists the health benefits with links to journal articles.   


Estrogen receptors (ERs): for a sex steroid to affect cell functions there must be receptors on or within the cell which effect functions.  “ERs are a group of proteins found inside cells. They are receptors that are activated by the hormone estrogen (17β-estradiol).[1]  . . .   Once activated by estrogen, the ER is able to translocate into the nucleus and bind to DNA to regulate the activity of different genes (i.e. it is a DNA-binding transcription factor). However, it also has additional functions independent of DNA binding” Wiki.  Given the similarity to sex hormone, a mimic of one will often enter the receptor but function significantly different, that is not according to the natural hormone which has evolved its functions over hundreds of millions of years and has evolved for the unique environment of each species.  Rarely, if ever, a synthetic or phytohormone (plant hormone) will perform in a mammal better than the natural hormone.  Moreover, plants haven’t evolved, for example, phytoestrogens to promote the health of the animals that graze upon them.  For this reasons, it is prudent to avoid them as they promote the survival of plants, there is a price, and those that market phytoestrogens aren’t looking for them. 


Estriol and estrone the other two common estrogens.  Estradiol is about 10 times as potent as estrone and about 80 times as potent as estriol in its estrogenic effects.  They have other functions such as down regulation some ot the estrogenic effects during pregnancy (estriol) and during and post menopause (estrone).  “Estrone can be converted into estradiol, and serves mainly as a precursor or metabolic intermediate of estradiol” Wiki. Both estrogens go to ER receptors there blocking estradiol, and have much lower estrogenic effects.  Estrone is a precursor to estradiol, though the rate of conversion as it changes with age has not been recorded.  Very little is know about their functions, and what little is known is their affinity for ER receptors.  Their action is far thinly researched, much thinner than estradiol.  There role appears to be regulatory upon estradiol during periods such as menopause, manache, pregnancy, and post menopause.


Progesterone (P4) is the most important of a class of hormones called progestogens.  [Wiki lists 12 major effects of progesterone.  They are structurally similar to the estrogens.]  The recognition of progesterone's ability to suppress ovulation during pregnancy spawned a search for a similar hormone that could bypass the problems associated with administering progesterone [low orally bioavailability, except in oil or lotion].  A progestin is a synthetic  progestogen that has pregestational effects similar to progesterone.  The two most common uses of progestins are for hormonal contraception (either alone or with an estrogen), and to prevent endometrial hyperplasia [excess growth in the uterus] from unopposed estrogen.  In mammals, progesterone, like all other steroid hormones, is synthesized from pregnenolone, which in turn is derived from cholesterol  in a very complex bio-system“ (Wiki 2009, more, journals ).  Statins in block 40% cholesterol synthesis also block the hormones and much more.  Lowering the production of cholesterol though profitable for pharma has many pathogenic health effects including those from lowering estrogens, testosterone, and progesterone.  Statins lowers only in very flawed clinical trials ischemic events.  Basic science on the vital subject of hormones is 95% driven by marketing, basic science is thin and mostly done decades ago.    


Bad pharma:  The Pharmaceutical industry’s (pharma) prime goal is the maximization of profits; thus, public’s health is their hype.  I call this tobacco ethics and science. To know how broken the system is read Marketing Science, on the FDA , how doctors are their pawns, and watch Prof. Angell.  The attack on HRT follows the pattern of eliminating an off-patent drug that reduces profits especially when they prevent chronic conditions (see above). 




[1] Hormones when not actives are stored either as a sulfate or bound to a protein typically SDGH or albumin

[2] The major violation has caused the plagues of age -related conditions, many of which not occur decades before becoming a senior, is in the consumption of sugar averaging over 10 times that consumed by societies eating a traditional diet going back  2 centuries. 

[3] Wikipedia GERP30, 4/2019



Natural HRT Benefits vs. Mare’s Urine Estrogen with MPA--the tragic differences


Setting the record straight Prempro vs. natural HRT --  for  more


Section II:  Tobaccos Science and Bad Press:  Prempro, one of the first HRTs[1], has been marketed since 1942 by Wyeth Laboratory (bought out by Pfizer in 2009).  It has been and still is the best-selling HRT.  A supposedly definitive study of HRT was done by the FDA’s drug research branch, National Institute of Health (NIH) (with undoubtedly a nod from pharma).  The Women’s Health Initiative (WHI) knowingly selected the worst formulation of HRT, Prempro.  NIH had the results of the Hormone Estrogen Replacement Study (HERS) UK completed in 1998 which used Prempro; moreover, earlier studies singled out (medroxyprogesterone) MPA as the cause for the  increased risk of breast cancer (Goodman & Gilman 2006, 1552).   Prempro consists of an estrogen cocktail derived from pregnant mare’s urine—7 unique mare estrogens-to which is added the synthetic progestin MPA.  (The cruel treatment of mares and subsequent slaughter was broadcast by Frontline.)  “Pregnant mare’s estrogens are the weak estrone (>50%), and the two mare estrogens, equilin (15-25%) and equilenin….  Mare (equine) estrogens such as equilin, that are foreign to the human body, have been shown, when compared to other studies, to have effects that are significantly worse than the natural estradiol[2].” MPA, the synthetic progestin used in Prempro, blocks most of the beneficial effects of estrogen--the natural progesterone doesn’t.  Using Prempro, the WHI found that compared to a placebo there was increased incidents:  heart attacks 29%, breast cancer 26%, pulmonary embolism 113%, strokes 41%, total deaths 15%, all cancers 3%; reduced incidents: hip fractures 34%  and colon cancer 37%.”   “MPA antagonizes this athero-protective effect [on coronary arteries]” at 1997.  Though “all causes of mortality were not effected”, the press highlighted risks for HRT (undoubtedly with a nod from their biggest advertiser[3]), & HRT sales plummeted.  The equine estrogen only arm of WHI had better results; more proof that adding MPA causes the harm.   Pfizer in 2010 settled a suit over breast cancer for $330 million or $150,000 per person.  Yet Prempro is still on the market (thank you FDA & pharma) and still first in sales.  Based on the WHI, NIH issued this warning on all HRTs: “…increased risk of myocardial infraction, stroke, invasive breast cancer, pulmonary emboli, and deep vein thrombosis in postmenopausal women… Estrogens with or without progestins should be prescribed at the lowest effective doses and for the shortest duration consistent with treatment goals…”  The warning is placed on all packages of HRT, and it is accepted as correct by most doctors and patients.   My doubts were confirmed when attending a lecture on the WHI given in 2002 at UCSD by Professor Dr. Robert Langer.  He explained to a large medical audience that the WHI Prempro results cannot be validly applied to other HRT formulas.  Over 50 years of research was not overturned; rather physicians and the public were tragically misled by the press, pharma, guidelines, and the NIH.  This is another example of regulatory capture.  Tobacco ethics guides pharma. 


CONFIRMATION: Set Up to Fail was published in the highly acclaimed science journal, Nature, 09/09/2010:  Is Nature ignorant of the vital fact that Prempro contains no progesterone, but instead the artificial progestogen Provera [MPA].  The other component is Premarin (conjugated estrogen), which is a very uncertain, patent mixture of substances from the urine of pregnant mares…. [equine (horse urine) estrogens] have crucially different effects.  Prempro is totally unrepresentative of any other product used for HRT purposes…. . Much of it was known before the NIH chose to use Prempro in its intended landmark study.  Using a study of the effects of Prempro to attack the entire use of HRT has, through needless fear, caused millions of women to forgo considerable benefits of HRT using better products.  This point has been repeatedly made by endocrinologists.   Why does Nature not know it?--END OF ARTICLE.


"I think that it borders on a tragedy that Premarin and Provera [the 2 compounds in Prempro] were chosen as the only HRT treatments [for the WHI Study]”.  Another researcher finds that Provera [MPA]--and no other progestin--blocks the mechanisms that allow estrogen to fight the brain's immune response to Alzheimer's….  Bruce S. McEwen Neuroendocrinologist of the Rockefeller University is unequivocally critical of the study: "I think that it borders on a tragedy that Premarin and Provera were chosen as the only HRT treatments."  “With Medroxyprogesterone [MPA] in Provera you are activating two receptors involved with cell division in the breast," she says, "and that's the culprit, not estrogen [for breast cancer].”  Recent research shows that Provera interferes with estrogen's ability to prevent memory loss and dementia. “Estrogen is able to protect neurons against toxic assaults that are associated with Alzheimer's disease," notes Roberta Diaz Brinton, a neuroscientist at the University of Southern California…. she found “that Provera--and no other progestin--blocks the mechanisms that allow estrogen to fight the brain's immune response to Alzheimer's”. This immune response wears away at brain cells and causes them to leak neurotransmitters such as glutamate, which overloads and kills neurons.”  Hormone Hysteria, Scientific American Sept. 2003.  Premarin, conjugated estrogen or conjugated equine estrogens[4].  Since it is from a pregnant mare, like with mothers they make enough of an estrone to block the non-pregnant most beneficial estradiol, namely estrone.  Thus there is a double whammy that of the progestin which is inferior to the natural progesterone and the estrone” Wiki Nov 2012. 


The 2008 study “Could transdermal estradiol + progesterone by a sager postmenopausal HRT?  A review confirms the criticism of the WHI studies through an extensive review of existing research, while at the same time strongly supporting the continued use of HRT in menopausal women because of lowering the risk of degenerative diseases such as osteoarthritis, rheumatoid arthritis, cardiovascular disease and their consequences, other benefits include reduced risk of sarcopenia, osteoporotic fractures, diabetes, hypertension, cognitive decline, sexual decline, and without the risks caused by the synthetic HRT such as deep vein thrombosis, pulmonary thromboembolism, and breast cancer.  This study has been lost in pharma dominated education and guidelines which has turned doctors into dupes of pharma.  Sadly and reluctantly, I have concluded that medical science has been replaced with marketing pants that is wearing the language of medical science.  Following the business imperative for quarterly profits pharma applies tobacco science and tobacco ethics thereby putting profits come before people.  We have the greatest black man-made health disaster dressed as the miracle of modern science.  The number of drugs not worth their side effects is the norm.  Until the national data banks for the real-world population are opened, the harm done and benefits caused by the weird chemicals called drugs won’t be known.  Our high sugar diet has damaged every cell, and thereby greatly increased our vulnerability.




[1] First was DES (diethylstilbestrol) a non-steroidal estrogen developed in 1938.  Like Fleming with penicillin, DES was not patented because Dodds felt that scientists were working for the pubic, and it was too important to deny cheap availability by patenting.  Animal studies had in the 1930’s exposed DES serious side effects; but the industry relied upon human trials, and the FDA on Sept. 19, 1942 approved DES though aware of the more reliable animal studies.  DES was marketed under 200 brand names.   Numerous claims were made such as producing healthier babies and preventing miscarriages.   In 1971 DES was found to cause a 40 fold increase in cervical & vaginal cancers.  Later studies found several internal genital abnormalities in the daughters and sons of mothers given DES.  26 years later In 1997 Eli Lilly stopped making and  marketing DES.   DES was also the standard treatment for advance prostate cancer for over 40 years.  The other early blockbuster HRT Prempro with the progestin MPA has been shown to increase the rate of growth of breast cancer.  So too does nonrethisterone and dienogest, but progesterone induces apoptosis, at.

[2] Equilin blocks E1 and E2 receptors and thus would reduce the effectiveness of natural estrogens.  Though Prempro and Premarin (just equine estrogen) are still the world’s leading HRT and ERT, no follow-up research was done because the financial incentive is to hide side effects. 

[3] Pharma’s  assault on HRT is driven by their profits for chronic conditions arising from osteoporosis, depression, arthritis,  Alzheimer’s disease and the assorted illnesses and conditions related to atherosclerosis especially  heart attacks, strokes, and  hypertension; an example of tobacco ethics.

[4] s estrone 51%, equilin 24%, 17 alpha dihydroequilenin 15%, 17-alpha estradiol 4%, equilenin 3.3%, and estradiol 1.1% at textbook.


Section III: BENEFITS OF HRT

Why are the sex steroids (sex hormones) so beneficial for those with hypogonadism?  I lean heavily upon our ancestors living in villages, for most there is incessant warfare with neighboring villages and/or clans.  The elderly being a burden because of their decline in functions to labor, produce children, and fight (males), this entails that biological systems that removes the elderly would be selected for.  The andropause and menopause occur in the 6th promotes their elimination.  Hormonal supplementation counters the steroids role in the aging process, thereby improving quality of life. 

Mitochondrial dysfunction:  This explains all the benefits below!  Mitochondria have sex hormone (including DHEA) receptors, that turn up the various processes that protect the mitochondria from damage by reactive oxygen and reactive nitrogen species.  Optimal mitochondrial functions entail an adequate supply of the energy molecule ATP, which is what fats and carbohydrates are used to make through their conversion acetyl-CoA and pyruvate in the cytosol and then transported into the mitochondria to make the essential ATP. EVERY PROCESS IN THE BODY RUNS ON ATP. Early, in 2018, I came to the realization that the long list of conditions associated with the western diet had as a starting point the reactive sugar fructose damaging mitochondrial DNA.  Subsequent investigation found that the sex hormones TTT and estradiol are mitochondrial protective re reactive chemicals, and this is the mechanism behind their long list of benefits.  Both steroids trigger a complex molecular mechanism that involves crosstalk between the mitochondria, nucleus, and plasma membrane, and the cytoskeleton plays a key role in these interactions. The result of this signaling is mitochondrial protection”, at Sept 2013. “Our results indicate that testosterone improves cell survival and mitochondrial membrane potential and reduces nuclear fragmentation and reactive oxygen species (ROS) generation.  These effects were accompanied by a positive regulation of neuroglobin, an oxygen-binding and sensor protein, which may serve as a regulator of ROS and nitrogen reactive species (NOS), . . .  these findings suggest that astroglia may mediate some of the protective actions of testosterone in the brain upon pathological conditions” at June 2016 and similar for cytoprotection and cardiac recovery after MI, at 2004.  Overall benefits through signaling and turning on DNA is covered in an 2011 seminal article.   All three very similar in structure hormones, testosterone, DHEA, and estradiol have similar protective functions.  Unfortunately, the industry that profits from illness has opposed their usage and does tobacco science to “educate” physicians and the public that hormonal interventions has major “risks” and minimal benefits, while at the same time ignoring studies that contradict their findings.  We have gone from the golden age of medicine back to the snake-oil era now dressed in the language of science and clinical trials.  The devil is buried in pharma’s details. Sadly I have come to realize the corruption worked by an industry that profits from illness and has created pill pushers and pill poppers—for some examples, and.         

 

Alzheimer’s disease with past long-term HRT, 7 vs 30 control.  Estrogen is neuro-protective by inhibiting oxidative damage.  Progesterone is also neuro-protective:  used in large doses following trauma “to limit central nervous system damage.”  Again MPA in WHI study increased risk of dementia, 40 cases of dementia versus 21 in the placebo group, at. .  A study of hypoxia and DHEA, TTT, and estradiol and their metabolite epiandrosterone (EPIA) found only EPIA neuro-protective. This helps to explain why the method why some have failed to find estradiol neuroprotective.      

 

Breast density maintained for women on HRT.  The difference has been repeatedly noted on mammograms. 

 

Cognitive Function: “There are plausible biological mechanisms by which estrogen might lead to improved cognition.”  Estradiol surpasses oxidative stress in the brain’s mitochondria, thus increasing ATP needed for optimal function, at 2007. 

Sexual Satisfaction: prevents vaginal atrophy, HRT improves sexual functionbetter, estradiol & testosterone, &.

Cancer breast et al risk decreased:  73% less for estradiol:   “in breast cancer 10 in treated group v 17 in control group.”   HRT after & also during breast cancer greatly increases survival, also ratio 0.28, and 53% increase-results would be better estradiol  with progesterone. “MPA (in Prempro) increases the risk of breast cancer” some progestins increase risk.  Contrary to pharma, estradiol  progesterone doesn’t  increase risk,  and when given following breast cancer over  2/3rd fewer deaths at 15 years HRT, and  also, also, same for uterine cancer.   HRT also prevent skin cancer.

Colon cancer: the reduction among current users RR = 0.55… users of 11 years or more RR of 0.54 [46% lower, also].” Estrogen and progesterone have beneficial effects for “esophagus, stomach, gallbladder, and intestines.”

Breast cancer survival:  Cancers in women who use HRT are often less advanced, and lower mortality has been reported in those who use HRT than in nonusers… The association of HRT with lower proliferation rate and smaller tumor size was exclusively caused by ER-positive tumorsat.  After diagnosis 72% higher survival: “The risk of death was lower among the HRT survivors; odds ratio 0.28…” at,  Also, breast cancer mortality rate of 5 per 1000 person years in HRT users compared to 15 in nonusers, at.  This was explained, along with the fact that women post-menopausal women on estradiol and those  were pregnant have a lower risk of breast cancer in that their estradiol and estriol blocker estrone (E1) stimulates cancer growth—at 1974.   For negative results, pharma used the progestin MPA (WHI study) which blocks the cancer protecting and CVD protecting effects of estradiol; other progestins could be similar; however, “progesterone combined with estradiol induces apoptosis [cancer cell death]” at.  So rather than go after the block the culprit estrone sulfate with E1-3-MTP (at 1993), pharma blocks both estradiol its health benefits and estrone. 

Cardiovascular disease (CVD) & MI: “estrogen lowered … 37% LDL …, extends life 2.1 years,” Braunwald, Heart Disease 5th Ed, 97, p 1708.  “HRT decreases CAD morbidity and CAD mortality … was 0.56 compared to subjects not taking estrogen” Braunwald 1142; another 50%, 16 vs 33, reduction in CHD.  Estradiol blocks oxidation of LDL to prevent atherosclerosis.  Estradiol completely reverses the effects induced by OX-LDL on the DDAH/ADMA/NO pathway,” Avoid MPA and LNG (levonorgestrel).   Another study found 26 MI deaths for estradiol vs. 56 for placebo (115%).  A meta-study found and a 50% reduction of Coronary Heart Disease.  Lowers hypertension risk.  Two AHA studies explain mechanisms of cardio arteries protection and Wiki,  also,   Angina pain is associated with low estrogen, treated.   Calcification of arteries is strongly associated with MI.  HRT lower calcification of coronary arteries—at, using Prempro.

Cholesterol effects, percentage of reduction in LDL with E 37%, with E + PA 46% (E is equine estrogen and PA is medroxyprogesterone Braunwald, Ed 6, Table 51-2).  Estrogen significantly protect LDL from oxidation at . “E2 at a concentration of 1 μmol/L inhibited LDL oxidation by 37% to 62% at the various concentrations of copper” at.  Oxidized LDL in the tunica media of the artery is held to by pharma to be the major cause for atherosclerosis and CVD.   I DO NOT SUBSCRIBE TO THE LIPID HYPOTHESIS, statins are poison, wrong cause, and more, expert’s review on statins as poison.

Diabesity, which is both Obesity & Diabetes:  the drop of estradiol increases LPL which regulates weight, distribution of fat, and activity.  Gary Taubes, Good Calories, Bad Calories, 398, Taubes Why we Get Fat, 90-91, and Wade at,  In the obese estrone is +40% at.   Weight related issues (metabolic syndrome, insulin resistance, & diabetes) are associated with drop in estradiol, at.  Likely mechanism is a reduction in the related hormone DHEA whose metabolite (7-oxo-DHEA) promotes significant weight loss (at) and is neuroprotective (at).  Note, JK takes DHEA 40 mg sublingually; it diminished appetite for one hour, mild stimulant and avoid first–pass over 95% metabolism by the liver which occurs with oral dose, no additional weight gain.     

Endothelial cell dysfunction prevented, the compromised performance of the single layer of squamous cells lining all the blood that form an interface between circulating blood content and interior tissue.  Their under-performance is responsible for over 95% of all cardiovascular disease.  Estradiol significant improves the performance of these cells at 1996, 1996.   Hormone replacement with estrogen has been shown to improve endothelium-dependent vaso-relaxation acutely in a number of animal models, including primate coronary arteries (97)at 1999—relaxation a measure of health.Endothelial function is abnormal in many postmenopausal women compared with premenopausal women, and in some postmenopausal women it can be enhanced by estrogen replacement therapy. This effect may increase with prolonged use” June 1998.   

Longevity:  Telomere numbers of units on the end of DNA are essential for cell longevity and functionality—see Wiki.  It has been shown both in animal and human studies that treatment with estradiol lengthens through action on telomerase the number of telomere units, see careful matched study of HT therapy, and, and, and, for animals.  This action on telomerase in part explains the many benefits from estradiol as to the protective effect in mitochondria. 

Macular degeneration, and hearing:  HRT resulted in a 36% reduction and other eye pathologies.  Hearing better.

Mental Health:  Estradiol like several hormones (DHEA and testosterone and probably others) have receptors in  some of the cells in the brain. For example, DHEA is produced in the brain.  Estradiol has been found to be effective in the adjunctive treatment of schizophrenia in women. It has been found to significantly reduce positive, negative, and cognitive symptoms, with particular benefits on positive symptoms.” Wiki 4/19.

Mitochondrial protection as antioxidant: “Estrogens have antioxidant properties which are due to their ability to bind to estrogen receptors and to up-regulate the expression of antioxidant enzymes via intracellular signaling pathways. . . . Recently, estrogen receptors were identified in mitochondria at 2010. This function is at the heart of E2 benefits.

Mood elevation and depression: “Numerous molecular and clinical studies have implicated estrogen in modulating brain function including that related to mood,” treatment of mood disorders and depression no additional weight gain.

NAFLD:  Non-alcoholic fatty liver disease) is also more common among men than women in all age groups until age 60, where the prevalence between sexes equalize.  This is due to the protective nature of estrogen,” Wiki.— diet's role.

Neurosteroids:  These brain-mainly glia cells produces sex steroids that are labeled “neurosteroids”, and have been found to exert important regulatory functions” at 2008.  Among the neurosteroids are pregnenolone, estradiol, testosterone, and DHEA and their storage form such as DHEAS and pregnenolone sulfate.  Those just listed I have I have extensively reviewed their literature.  There are over a dozen other neurosteroids.  As a senior I take sublingually or in lotion 3 of those hormones.  They reduce the risk of for age related neurodegenerative conditions and slow the rate of cognitive decline (contrary to pharma’s warnings and the belief of most physicians).      

 

Osteoporosis and bone remodeling: “Bone loss increases after menopause due to lower levels of estrogen.,. [causes removal of ovaries” Wiki  Esterified estrogens produced significant increases in bone mineral density (lumbar spine, hip).   54.2% greater spinal mineral.  1 of 4 white women over the age of 60 had spinal compression fractures associated with osteoporosis. One woman of 5 will fracture a hip by the age of 90,” and even more will have knee replacement operations.   Bone gain from long-term HRT, also; estradiol's role. Numerous journal articles hold that progesterone work with estradiol to increase remodeling of bone, at, and, and.  Estradiol slows the loss of bone calcium and progesterone increase the rate of calcium replacement.  Bisphosphonates drugs increase bone density by adding unnatural phosphate to the bones which result in an increased brittleness, and “they disrupt intracellular enzymatic functions needed for bone resorption” and they have other major side effects. Including atrial fibrillation.    

Osteoarthritis (OA): When both incident and progressive radiographic knee OA cases combined, “current ERT [estrogen only replacement therapy] use had a 60% decreased risk compared with never use”.    Progesterone is most important.

Rheumatoid Arthritis (RA):  “HRT was well tolerated, increased well-being, reduced articular index and increased lumbar spine bone density over a one year period in postmenopausal women with RAalso, & lowers RA CVD deaths.

Parkinson’s disease,” loss of estrogen resulted in decrease neuron density in the substantia nigra (structure of brain damaged by Parkinson’s disease), and restoration of estrogen in increased density” at, and.  Again MPA exacerbates condition & risk, at.  Pharma of course does junk science to show that HRT does not affect the course of the disease. 

Programed death & longevity through menopause is to remove elderly women from the community, thus the precipitous decline in health of women after menopause.  To slow this process requires the taking of natural HRT.

Sarcopenia age related loss of skeletal muscle mass with age is associated with low level of estrogen & testosterone in 22.6% in older postmenopausal women not receiving estrogen or TTT.   TTT prevents and reverses sarcopenia, and; however HRT alone does not protect against muscle loss which is why I would add TTT to the compounded formal.    About 10% of estradiol is converted to testosterone by the body for its androgen (muscle building) effect.     

 

Skin healthier American Journal of Clinical Dermatology & more hair, hair, hair.    Studies of postmenopausal women indicate that estrogen deprivation  is associated with dryness, atrophy, fine wrinkling, poor healing, epidermal thinning, declining dermal collagen content, diminished skin moisture.  The decrease was preventable by the use of HRT.” “The mean collagen content in the skin was … found to be 48% greater”, slows skin aging, also, and less skin cancer, 2008.

Urinary Tract Infections Recurrent (UTI), also urinary urgency, urogenital & vaginal atrophy are associated with low estrogen in post-menopausal women.  A meta-analysis of 8 quality studies found the placebo group 2.5 times more likely to have a subsequent UTI. Topical administration most effective; however for vaginal atrophy estradiol tablets.

Venus Thrombosis:  an 8% reduction in risk of with esterified estrogen while those on Prempro had a 65% elevated risk JAMA 04, and; a 23% reduction exogenous estrogen (5.1% of cases versus 6.3% control cohort).

10 Reasons for HRT:  Menopause Int. & Oncology:  Both list the above benefits, and the latter advises HRT for survivors of breast cancer because of “a 70% reduction in the risk of death” during the 15 years, also.

 

The 4 other major sex hormones (DHEA, progesterone, testosterone, and pregnenolone):  What is said of estradiol as to positive effects applies to testosterone, they follow a similar evolutionary path, but for the degree of androgen effect (only about 10% of estrogen is converted to testosterone, thus its lower androgen effect).   In general, the cell types which have estrogen receptors have receptors for other sex steroids, and often the combination is superior to supplementation with just one of those steroids—see below recommendations. 

 


Section IV, What I would do if a woman:  NHRT is part of nature’s clock.  NHRT sets the body’s clock to premenopausal and thereby reduces the rise for age-related chronic conditions.  The low level of estradiol causes the precipitous decline after menopause.  Average life extension with long-term NHRT is over 6 year based on above benefits and the Danish long-term trial, which the BMJ reprinted a decade later to get the message out.   NHRT must be applied topically as a cream from a compounding pharmacy and not as a pill, since when taken orally the nutrients and other substances absorbed by the intestines travel through the hepatic portal vein to the liver where the estradiol is converted to estrone, the contraceptive form of estrogen.  Estrone goes to the ER-alpha and ER-beta estrogen receptors and blocks estradiol activity.  The creams should contain at least 15 mg of estradiol and 100 of progesterone since absorptions are but 10%.  If some is applied vaginally, the absorption is about 30%.  My former wife uses 30-gram of 0.15% monthly of lotion from the compounding pharmacy to which she applies 1/4th teaspoon (1 grams) over her upper torso while still wet following her shower (this permits by spreading out the lotion better absorption). If concerned about muscle strength, add 30 mg of testosterone in lotion to reverse sarcopenia, androgen deficiency, & to improve libido without reduction in estradiol.  Wikipedia (4/19) lists bioavailability of E2 at <5%.  The same applies to the other sex steroids.  I take testosterone since 2004 topically as cream 375 mg daily, and DHEA sublingually 100 mg since 2002.  60% of estradiol is bound to albumin and 38% to SJBG, and 2% is free.   Pregnenolone and DHEA are stored as sulfates, and the others are bound on proteins.   


What to avoid and why:  True to profits-first, corporate tobacco ethics, pharma offers 1) HRT in too low a dose; 2) Some oral formulations of estrogen don’t deliver estradiol, but rather the inferior estrone—which works as birth control, but lacks estradiol healthful benefits; 3) synthetic estrogens, horse estrogen, and synthetic progesterone (progestins) of questionable value and safety; 4) Avoid pharma’s HRT in that they are probably too low a dose and other tricks.  For example, in the US, Novo Nordisk markets is Vagifem, a vaginal inser; it is 10 mcg (yes, micrograms, 1/10th of a mg) of estradiol.  At that dose it possible reduces vaginal atrophy, but certainly won’t reduce risk for ischemic events, cancer, Alzheimer’s diseases and so on.  Their product marketed in 1990 had 2 mgs of estradiol; it in a 11 year follow-up had 15 deaths compared to 26 in the placebo group.  Prescription HRTs are likely to be too low a dose and/or with a pathogenic progestin.  See what my ex-wife takes below, a better choice; 5) human estrogens estrone (E1), Estriol (E3), estetrol (E4) which are less bioactive and they block some of the action of estradiol, the best estrogen.  Most doctors will look on their computer and prescribe as a compounded lotion E3, E2, and progesterone.  E3 blocks the benefits of E2 and has the side effects of tender breasts and nausea.[1] Probably the same with the addition of E1 and E4; 6) Physicians responding to a patient’s request for compounded lotion will likely use their computer for the formula.  It will consist of a cream which will have both E2 and E3.  E3 blocks E2, and causes blotting and other side effects.  I have received reports from both Canada and the US of patients getting the same combination—thank you, pharma; 7). For hot flashes, NIH guidelines include a major tranquilizer (SSRI),estrogen blockers such as Tamoxifen, the bisphosphonate Fosamax, estrone (as Estragyn) which is a very weak from of estrogen that blocks estradiol, and Ropinirole a dopamine agonist thus promotes lethargy and depression—all of them have made my do not take list.   “Current research shows that the transdermal route of estradiol administration can also be advantageous for women with diabetes, hypertension and other cardiovascular risk factors, as those risks increase with advancing age” Wiki 2018, at 2013, 2008. “Oral HRT is associated with an increased risk of venous thromboembolism (VTE), gallbladder disease and possibly stroke.  The increased occurrence of all these events can be prevented by the use of the transdermal route of estradiol administration; this route seems also advantageous for women with diabetes, hypertension and other cardiovascular risk factors, and also especially with advancing age” at.  This doesn’t apply to transdermal application which avoids the high level of metabolic products generated by the liver that are causal for those events, at 2008.  If I was a woman, I would tell my physician I don’t believe those risk apply to NHRT, and what risks there are is outweigh by benefits, then give him a copy 2010 journal article.  There is a major difference between a pill and a lotion, due to the action of the liver upon estradiol when taken orally.  I’d tell him I observed the benefits in a friend & a relative and want the same.


Beware of hormone balancing; some doctors are milking the patient.  The evidence for this is weak for postmenopausal women.  Avoid “bio-identical” plant estrogens and progesterones—they aren’t identical to human sex hormones.  These hormones occupy receptors with uncertain action and possible block benefits, like MPA, and most have low bio-availability and even lower bioactivity.   The evidence for sequential HRT is moderate, but it has a lower compliance because of vaginal bleeding (at 1997) and it must be taken as a pill which entails the conversion of estradiol to estrone (see above).  There is a lack of quality clinical trials on them.[2]  However, both hormone balance and sequential HRT are significantly better than going without HRT.  Estrogen is involved in both weight regulation and fat distribution.  Low estrogen entails for most a gain in unhealthy visceral (adnominal) fat.  Reset your bio-clock with NHRT, fix your diet, learn about the corruption caused by pharma (on YouTube), and why doctors are their pharma’s pawns.  For testimonials and more on osteoporosis, link.  


Some of the neuroleptic psychiatric drugs promote significantly catabolism of E2 (and possible other estrogens) through upregulation of P-450 cytochrome, therefore a higher dose would be needed for the estrogens.  The research was only on a few of those drugs, at P 290.   Though another topic, in most cases it is best to avoid the neuroleptic drugs—another topic.  If you must use drugs to reduce boredom and desire to reduce cognitive functions, it is better to use marijuana.  Finally, it is best to stay clear of pharma’s HRT; the last time I looked at what was offered (2015), I wasn’t pleased.  In an era of search for drugs, there are 197 pounds listed in Wikipedia that are hormones, hormone derivates, or have hormonal action; a gross example of searching for products. There are 159 combinations of hormones, 130 estrogen esters, and 67 estrogens.  Money shouts, and basic science whimpers.  Not surprisingly with pharma intrusion into education, doctors are dupes of pharma, thus they are true believers who don’t know what is best or harmful.   


 


 


 


^^^^^^^^^^^^^^^^^^  Non-technical summation    ^^^^^^^^^^^^^^^


Natural Estrogen (Estradiol) with progesterone NHRT:  What every woman should be taking because of the numerous, major health benefits, benefits that would slash pharma’s profits.  Of the 4 natural estrogens only estradiol (E2) has major health benefits.  Two--estriol (E3) and estetrol (E4)--are found in pregnant women and block estradiol.  Unfortunately for women, the addition of E3 to E2 (estradiol) in compounded formulas has made the computer of physicians and is commonly included in the prescription.  This inclusion blocks the positive effects and increases side effects—more workings of pharma’s KOLs.  Big pharma being against hormone replacement therapy (HRT) markets ineffective products including those containing estriol and estetrol, and estradiol at too low a dose & with inferior progestins such as in the best-selling Prempro.  Prempro, a combination of estrogen derived from pregnant mare’s urine and the progestin MPA.  The biological effects of mare’s estrogens are different than human estrogen and MPA blocks most of the positive effects of estrogen.  Thus the results of the major WHI study funded by the FDA apply only for Prempro[3].  Nevertheless he FDA warns that HRT has only one valid medical use, to manage hot flashes, and should be used at the lowest dose for the shortest time.  Thus pharma has used marketing science & guidelines to overturn 4 decades of positive results for HRT:  Alzheimer’s 83%, Heart attacks 51%, Coronary Heart Disease 50%, Colorectal Cancer 46%, Breast Cancer 73%, Thrombosis 8%, Macular Degeneration 65%, osteoporosis fractures 90%, & prevents arthritic join destruction, firmer breasts, healthier skin (less wrinkles, thicker, 48% more collagen), reduces hair loss, improved cognitive function, less depression and mental illness, and a general feeling of well-being with increased libido.  These results occur because estrogen & progesterone receptors set the body to “premenopausal” maintenance.  Tribal survival benefits from elimination of the elderly, thus we have the reduction in testosterone and estradiol to promote that end.  The lack of estradiol (and possible progesterone) cause the precipitous decline in health of women after menopause.  Life extension with long-term NHRT is over 6 years, and twice that with a low sugar diet.  Progesterone (P4), the major progestogen, is similar to estrogen--they work together.  It has numerous benefits, while some of the artificial progestins are clearly harmful (such as stimulating the growth of breast cancer).  Synthetic progestins often interact with and transactivate androgen, mineralocorticoid, glucocorticoid or growth hormone receptors”, at 2008, and none have been adequately researched as to side effects.  Like testosterone, estradiol taken at higher dose has more benefits (this is distinguished from oral estrogens which prevent pregnancy by producing effects like in pregnancy, which is why a lower dose is better tolerated.)   A sufficient dose is available only from a compounding pharmacy (15 mg of estradiol plus 100 mg of progesterone) in a lotion obtained per application (there is a 10% absorption rate with topical hormones).  For a month’s supply have prepared 60 gram of  lotion, application of 1/4th teaspoon which is 2 grams.  Apply widely as possible over the torso, back, shoulders, underarms, and face using water and rubbing it in to promote better absorption.  Ideal free-serum estradiol level is 200-500 pmol/L.  Plant sources for HRT are not natural and are metabolized by the liver on first pass from the digestive system.  These hormone mimics fail to perform well and have adverse consequences (see MPA above).  The mimic can occupy sites that estradiol would go to and block its action.  Doctors who follow the Wiley Protocol are other methods of hormone balancing for post menopause women are milking the insurance and patient, and it lacks convincing scientific evidence.

“Current research shows that the transdermal route of estradiol administration can also be advantageous for women with diabetes, hypertension and other cardiovascular risk factors, as those risks increase with advancing age.[4] Wiki 2018, and at 2013.  Oral HRT is associated with an increased risk of venous thromboembolism (VTE), gallbladder disease and possibly stroke. The increased occurrence of all these events can be prevented by the use of the transdermal route of estradiol administration; this route seems also advantageous for women with diabetes, hypertension and other cardiovascular risk factors, and also especially with advancing age” at.  Tell your physician you are aware of risks and are convinced of benefits of NHRT applied topically is safe; then give him a copy 2010 journal article.  Tell him you observed the benefits in a friend & a relative and want the same.  Most doctors will comply with your request.



[1] “Estriol is an estrogen, or an agonist of the estrogen receptors, ERα and ERβ. It has been found to possess 11–14% and 18–21% of the relative binding affinities of estradiol for the human ERα and ERβ, respectively, while its relative transactivational capacities at these receptors were 11% and 17%, respectively” Wiki 4/19.  Thus E3 about 1/6th the effect of estradiol & much more side effects.

[2]There is weak evidence that the human body can convert its active ingredient.  And they are sometime not natural:  diosgenin, the plant steroid, is chemically converted to produce several steroid and sold as natural, see Wiki, and for more on progesterone, Dr. Lee. Moreover, these natural chemical are generally not tested on animals for toxicity, or purified to remove other compounds in the plant extract.  For a big window on plant toxins see the work of Prof. Bruce Ames, his links, very possible the leading authority.   

[3]   Prempro has been the leading selling HRT since the mid 40s in the US, and it still is.  The issues with MPA and mare’s urine estrogens has been known for decades by scientist including those in the FDA as inferior of the other HRT & natural HRT.  Because of birth control pills, HRT, and the possibility that an estrogen would protect men—as it does women—from cardiovascular disease, there has been thousands of published articles on the estrogen and progesterone family of hormones.   Unfortunately the FDA acts to promote products for pharma while minimally regulating in the public’s interest—see Consumer Report’s article, and also. 



^^^^^^^^^^^^^^^^^^  Non-technical summation    ^^^^^^^^^^^^^^^


Natural Estrogen (Estradiol) with progesterone NHRT:  What every woman should be taking because of the numerous, major health benefits, benefits that would slash pharma’s profits.  Of the 4 natural estrogens only estradiol (E2) has major health benefits.  Two--estriol (E3) and estetrol (E4)--are found in pregnant women and block estradiol.  Unfortunately for women, the addition of E3 to E2 (estradiol) in compounded formulas has made the computer of physicians and is commonly included in the prescription.  This inclusion blocks the positive effects and increases side effects—more workings of pharma’s KOLs.  Big pharma being against hormone replacement therapy (HRT) markets ineffective products including those containing estriol and estetrol, and estradiol at too low a dose & with inferior progestins such as in the best-selling Prempro.  Prempro, a combination of estrogen derived from pregnant mare’s urine and the progestin MPA.  The biological effects of mare’s estrogens are different than human estrogen and MPA blocks most of the positive effects of estrogen.  Thus the results of the major WHI study funded by the FDA apply only for Prempro[1].  Nevertheless he FDA warns that HRT has only one valid medical use, to manage hot flashes, and should be used at the lowest dose for the shortest time.  Thus pharma has used marketing science & guidelines to overturn 4 decades of positive results for HRT:  Alzheimer’s 83%, Heart attacks 51%, Coronary Heart Disease 50%, Colorectal Cancer 46%, Breast Cancer 73%, Thrombosis 8%, Macular Degeneration 65%, osteoporosis fractures 90%, & prevents arthritic join destruction, firmer breasts, healthier skin (less wrinkles, thicker, 48% more collagen), reduces hair loss, improved cognitive function, less depression and mental illness, and a general feeling of well-being with increased libido.  These results occur because estrogen & progesterone receptors set the body to “premenopausal” maintenance.  Tribal survival benefits from elimination of the elderly, thus we have the reduction in testosterone and estradiol to promote that end.  The lack of estradiol (and possible progesterone) cause the precipitous decline in health of women after menopause.  Life extension with long-term NHRT is over 6 years, and twice that with a low sugar diet.  Progesterone (P4), the major progestogen, is similar to estrogen--they work together.  It has numerous benefits, while some of the artificial progestins are clearly harmful (such as stimulating the growth of breast cancer).  Synthetic progestins often interact with and transactivate androgen, mineralocorticoid, glucocorticoid or growth hormone receptors”, at 2008, and none have been adequately researched as to side effects.  Like testosterone, estradiol taken at higher dose has more benefits (this is distinguished from oral estrogens which prevent pregnancy by producing effects like in pregnancy, which is why a lower dose is better tolerated.)   A sufficient dose is available only from a compounding pharmacy (15 mg of estradiol plus 100 mg of progesterone) in a lotion obtained per application (there is a 10% absorption rate with topical hormones).  For a month’s supply have prepared 60 gram of  lotion, application of 1/4th teaspoon which is 2 grams.  Apply widely as possible over the torso, back, shoulders, underarms, and face using water and rubbing it in to promote better absorption.  Ideal free-serum estradiol level is 200-500 pmol/L.  Plant sources for HRT are not natural and are metabolized by the liver on first pass from the digestive system.  These hormone mimics fail to perform well and have adverse consequences (see MPA above).  The mimic can occupy sites that estradiol would go to and block its action.  Doctors who follow the Wiley Protocol are other methods of hormone balancing for post menopause women are milking the insurance and patient, and it lacks convincing scientific evidence.


“Current research shows that the transdermal route of estradiol administration can also be advantageous for women with diabetes, hypertension and other cardiovascular risk factors, as those risks increase with advancing age.[4] Wiki 2018, and at 2013.  Oral HRT is associated with an increased risk of venous thromboembolism (VTE), gallbladder disease and possibly stroke. The increased occurrence of all these events can be prevented by the use of the transdermal route of estradiol administration; this route seems also advantageous for women with diabetes, hypertension and other cardiovascular risk factors, and also especially with advancing age” at.  Tell your physician you are aware of risks and are convinced of benefits of NHRT applied topically is safe; then give him a copy 2010 journal article.  Tell him you observed the benefits in a friend & a relative and want the same.  Most doctors will comply with your request.




[1]   Prempro has been the leading selling HRT since the mid 40s in the US, and it still is.  The issues with MPA and mare’s urine estrogens has been known for decades by scientist including those in the FDA as inferior of the other HRT & natural HRT.  Because of birth control pills, HRT, and the possibility that an estrogen would protect men—as it does women—from cardiovascular disease, there has been thousands of published articles on the estrogen and progesterone family of hormones.   Unfortunately the FDA acts to promote products for pharma while minimally regulating in the public’s interest—see Consumer Report’s article, and also. 



Why Natural HRT, which estrogens, higher dose, and non-sequential


There are 4 superior choices for natural hormone replacement therapy (NHRT).   1) that of estradiol and progesterone; 2) a sequential uses of those hormone to mimic the women’s premenopausal cycle;  3) to take all 3 natural estrogens plus progesterone[1], and 4) to take them sequentially.  What is the evidence to support these choices?  Unfortunately, dispositive quality evidence is lacking:  no long-term clinical trials; nor are there short-term clinical trials.  The reason is simple, the profit margin in insufficient on off patent drugs to justify such trials.  Products natural to the body cannot be patented (with a few exceptions).  Contributing factor:  in the golden age of medicine, when there was still significant amount of university ran and clinical trials with just mere funding by pharma, progesterone was available only as a topical cream (not orally active).  Today that has changed, and like CoQ10 it is available in an oil based capsule micronized.  For these reasons the evidence for NHRT is mainly anecdotal.  The second source for evidence is population studies (epidemiological), but nearly all of them have a major flaw, they gather the evidence from all women on HRT, independent of formulation.  A few epidemiological studies separate women according to type of products, & a few clinical trials are for one product.[2]  These provide evidence suggestive that 1 of the 4 choices could be better. 


So why do I favor # 1), non-sequential progesterone with estradiol?  First, estradiol has been used in a number of preparations with excellent results.  In the French epidemiological study (EN3) estrogen showed no increase in breast cancer; & Prempro the greatest increase (due to the progestin MPA).  E3N study supports the use with estrogen with progesterone and not a progestin.  Second progesterone and estradiol work together in the body, thus to use a synthetic form, called a progestin, has consistently resulted in lower benefits—see MPA example above.  Third, for those using a better progestins, their results were superior to using only estradiol, ethinyl estradiol, and esterified estrogen[3], this favors the combination NHRT. Fourth those who used estradiol and testosterone (common in Europe in the 1980-90s) instead of synthetic progestin had very good results; this also supports the use of progesterone.   Fifth, there is no clinical evidence supporting comparable benefits from the other forms of estrogen comparable to those from estradiol; this supports the use of estradiol.  Sixth, the laboratory work testing with estradiol indicates that it is the most important of the 4 estrogens.  Seventh in the Danish study of the sequential high-dose (tri-cyclic) Trisekvens[4] (a product only available in Europe), the results were excellent.  Eight, compliance issue because of mild side effects of nausea and break-through bleeding like those of a menstrual period.  Ninth, the paucity of evidence supporting for postmenopausal women a need for having cyclic hormones[5].   Tenth, cyclic NHRT would cost more and is less convenient to take.  Eleventh, if I in recommended sequential, some woman would find a doctor who charges many times more for monitoring blood hormone levels and providing a custom balanced hormone cocktail based on her blood work.  This lacks sound science.  Conclusion:  Thus recommend #1, NHRT of estradiol with progesterone from a compounding pharmacy, 2 mg estradiol and 100 mg of micronized progesterone in oil as a capsule. 




[1] Dr. Jonathan V. Wright in Natural Hormone Replacement (1997) recommends all 3 hormones.

[2] Note, the large trials government funded trials (HERS and  WHI) are designed to show HRT as dangerous, since pharma opposes for business reason HRT.

[3] Esterified estrogen and ethinyl estradiol are commonly used instead of estradiol because of longer half-life--still available. They are  derivatives of estradiol, of which for esterified estrogen there are over 30--a way for pharma to obtain patents of exclusivity.  I consider these 2 equivalent to estradiol, though some of these forms must be inferior.   

[4]  The women in the treated group with an intact uterus started treatment with 2 mg synthetic 17-β-estradiol for 12 days, 2 mg 17-β-estradiol plus 1 mg norethisterone acetate for 10 days, and 1 mg 17-β-estradiol for six days (Trisekvens; Novo Nordisk, Denmark). http://www.bmj.com/content/345/bmj.e6409?etoc= .  “Because of break-through bleeding with sequential Trisekvens, non-sequential combined HRT form of Trisekvens was better received.” At.  

[5] Over 95% of HRT products are not sequential and the literature does not indicate an associated problems.  Nor are the benefits exceptional favorable from sequential Nordisc compared to the best of epidemiological studies. 



Why the higher dose of estradiol?  This is comparable to that used in Trisekvens which had excellent results.  In the 1960s through the 1980s the higher dose of estradiol was the norm, and during that period the numerous benefits were uncovered in epidemiological studies; thus higher dose is better.  Second, in men higher dose testosterone[1] has significantly greater health benefits, more evidence for a higher dose of estradiol.  Third, pharma in their opposition to these healthful hormones recommends the lowest dose, still more evidence that the higher is better.   


Why natural?  The goals is to restore youthful benefits and avoid age related conditions, thus to restore hormones to youthful levels.  Natural products have evolved to work in the body through receptors and complex feedback systems; thus synthetic chemicals don’t function as well.  Natural hormones have lower risk of side effect (for which the reporting system is broken)[2].  Of the over 100 synthetic hormones, there is no evidence that they work better, and only one has very good results in a clinical trial—unfortunately the Danish product is not licensed in the US. 


Why not branded drugs for HRT?  With the support of the NIH, pharma opposes HRT since 1990s, thus current products have various issues:  1) dose is too low for most of the healthful benefits; viz. not equivalent to 2 mg of estradiol.  Fernhrt has only .25 mcg of ethinyl estradiol (1/8th the recommended 2 mg).  Estragyn (estrone) is a 0.1 gm vaginal cream; but estrone is far less bioactive than estradiol, and the absorption rate is under 25%.  2)  A number of products are not estrogen, but estrogen antagonists (they occupy estrogen receptors on the cells and thus block estradiol’s action).  Tamoxifen is one of several estrogen antagonists marketed as HRT.  3) Estrogens with harmful progestins: Femhrt has the progestin norethindrone acetate, and Prempro has the progestin MPA.  4) Use less bioactive estrogens such as estrone, estriol, derivatives of the estrogens, and mare’s estrogen in Premarin.  5) For hot flashes several tranquilizers of the SSRI and dopamine agonist types have been approved, and many more are used off-label. 


Problem of finding a doctor who will prescribe HRT as recommended.  Be prepared with an answer when your doctor suggests that you try something else first.  You can refer to books, such as Natural Hormone Replacement (the Amazon reviews has good material). Ask him to read an article in Menopause Internal Journal which I have pasted with link.  Refer to the experience of friends, or other articles you have read.  And you can simply tell him that the 40 years of positive journal literature was not overturned by the flaw Women’s Health Initiative Study (WHI) which used estrogen from mare’s urine along with MPA as a progestin, which has been known to block some of the benefits of estrogen and increase risk for breast cancer. 


Nearly all doctors have fallen for the anti-HRT myths:  promotes breast cancer, and benefits aren’t worth the risks.  As argued at HRT, this is false for NHRT and most formulations of HRT.  Thus to get HRT or NHRT long-term (not just for hot flashes) requires a physician who is willing to do what once was the norm before 2002.  The earlier studies on HRT were not wrong.  I about 3/4th of doctors will write a prescription for NHRT for their regular patient after lecturing on the risks and a referral for a mammogram.[3]  He is protecting himself from possible litigation.  Copy this 2010 journal article Ten Reasons to be Happy About Hormone Replacement Therapy: A Guide for Patients to MS word and print it.  Read it before seeing him, and give him a copy.  These hormones are part of nature’s clock for us to die in the 7th decade.  The low estradiol & progesterone is the reason for the precipitous decline in health of women after menopause.  Sending a message to your body that you are premenstrual; it is worth the effort to jump through a few of pharma’s hoops. 


Progestins are of uncertain effects:  The use of progestins, in particular medroxyprogesterone acetate, in treating post-menopausal symptoms have been associated with increased risk of blood clots[45] and breast cancer in a study carried out by the Women's Health Initiative. While the study did not involve dydrogesterone, it is possible, but not certain, that it too increases these risks.[46]   [The blood clots a key risk factor for MI, explains why with Prempro used in the WHI) there was no reduction in MI—while with other formulas of HRT the reduction is 35% or greater.  The WHI has a second flaw in that of 55% equine estrogen, which is of uncertain consequences, thus the estrogen alone arm of the study is applies only to Premarin —jk.]  https://en.wikipedia.org/wiki/Dydrogesterone


 


^^^^^^^^^^^^^^^^^    http://www.sciencedirect.com/science/article/pii/S0378512203003463    


Abstract


Our in vitro results indicate that not all progestogens act equally on breast cancer cells. Some progestogens (medroxyprogesterone acetate (MPA), norethisterone acetate (NETA) and dienogest) alone or combined with estradiol (E2) stimulate proliferation of breast cancer cells, while others (dihydrodydrogesterone (DHD), the active metabolite of dydrogesterone, tibolone and progesterone (Prog)) alone or combined with estradiol induce apoptosis [prevents cancer].  Further pharmacological and clinical studies should be initiated to evaluate these findings in vivo.


 


^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^

The women in the treated group with an intact uterus started treatment with 2 mg synthetic 17-β-estradiol for 12 days, 2 mg 17-β-estradiol plus 1 mg norethisterone acetate for 10 days, and 1 mg 17-β-estradiol for six days (Trisekvens; Novo Nordisk, Denmark). http://www.bmj.com/content/345/bmj.e6409?etoc= .  “Because of break-through bleeding with sequential Trisekvens, non-sequential combined HRT form of Trisekvens was better received.” At.  



[1]  Testosterone is structurally the same as estradiol but for one group on the molecule.  In the body women convert some of their estradiol to testosterone so that there level is about 1/10 that of a man’s.  Men convert some of their testosterone to estradiol.  

[2] Progestins are of uncertain effects:  The use of progestins, in particular medroxyprogesterone acetate, in treating post-menopausal symptoms have been associated with increased risk of blood clots[45] and breast cancer in a study carried out by the Women's Health Initiative. While the study did not involve dydrogesterone, it is possible, but not certain, that it too increases these risks.[46]   [The blood clots a key risk factor for MI, explains why with Prempro used in the WHI) there was no reduction in MI—while with other formulas of HRT the reduction is 35% or greater.  The WHI has a second flaw in that of 55% equine estrogen, which is of uncertain value, thus the estrogen alone arm of the study is applies only to Premarin —jk.]  https://en.wikipedia.org/wiki/Dydrogesterone

[3]  Men have a similar problem in obtaining a testosterone of sufficient dose, which entails using a compounding pharmacy. 


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http://en.wikipedia.org/wiki/Medroxyprogesterone_acetate

The Women's Health Initiative investigated the use of MPA and conjugated equine estrogens compared to placebo. The study was prematurely terminated when previously unexpected risks were discovered, specifically the finding that though the all-cause mortality was not affected by the hormone therapy, the benefits of the hormone replacement therapy (reduced risk of hip fracture, colorectal and endometrial cancer and all other causes of death) were offset by increased risk of coronary heart disease, breast cancer, strokes and pulmonary embolism. MPA increases the risk of breast cancer, dementia and thrombus when used in combination with conjugated equine estrogens to treat the symptoms of menopause.[3] 

MPA is associated with an increase in depression.  MPA may cause adrenal suppression and interfere with carbohydrate metabolism but does not cause diabetes. MPA can cause weight gain, worsen diabetes mellitus and edema (particularly of the face).   MPA may cause reduced bone density


For hormone replacement http://healthfully.org/fhr/; for women health issues http://healthfully.org/highinterestmedical/.  Both library of journal articles and more.

INTERNAL SITE SEARCH ENGINE by Google

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Disclaimer:  The information, facts, and opinions provided here is not a substitute for professional advice.  It only indicates what JK believes, does, or would do.  Always consult your primary care physician for medical advice, diagnosis, and treatment.