Estrogen Basics:  Estrogens (Wikipedia) are a group of related compounds named for their importance in the estrous cycle of humans and other 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,^[1] and the suffix -gen, meaning "producer of".  Estrogens are synthesized in all vertebrates^[2] as well as some insects.^[3]  Like all steroid hormones, estrogens readily diffuse across the cell membrane. 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.^[5]   The three major naturally occurring estrogens in women are estrone (E1), estradiol (E2), and estriol (E3).  Estradiol (E2) is the predominant estrogen during reproductive years both in terms of absolute 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 effect.  Estrone is secreted by the ovary, adipose [fat] tissue, and placenta.  As a sulfate it acts as a reservoir that can be converted as needed to estradiol.  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.  Thus, 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 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 corpora lutea.  Some estrogens are also produced in smaller amounts by other tissues such as the liver, adrenal glands, and the breasts.   Androstenedione has weak androgenic activity [muscle building] and is the predominant precursor for the more potent androgens such as testosterone as well as estrogen.   Among estrogen’s over 2-dozen bodily functions are those of lowering the remodeling threshold, thus preventing osteoporosis.  Estrogen prevents cardiovascular disease by lowering cholesterol levels, and by reducing inflammation and oxidative damage to LDL [bad cholesterol].  Inflammation and oxidative damage are causal factors for cognitive decline, Alzheimer’s disease and other conditions.  Estrogens circulate in the blood in association with proteins including sex hormone binding globulin and albumin (50-80%), and a significant portion is in the form of a sulfate.  It is distributed in most tissues, especially the breast, uterine, vaginal, and has a high affinity to adipose tissue.  Estrogens are metabolized in the liver and excreted as metabolites by the kidney.  Estradiol during menopause sharply declines; but the levels of total and free testosterone, as well as dehydroepiandrosterone sulfate (DHEAS) and androstenedione appear to decline gradually with age. The limited effectiveness of plant type estrogens is due to their lower bio-activity and first-pass metabolism by the liver.  Progesterone belongs to a class of hormones called progestogens, and is the major naturally occurring human progestogen. 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 bioavailability when administered orally, except in oil).  A progestin is a synthetic^[1] progestogen that has progestational effects similar to progesterone.^[2] The two most common uses of progestins are for hormonal contraception (either alone or with an estrogen), and to prevent endometrial hyperplasia [excess tissue in the uterus] from unopposed estrogen in hormone replacement therapy.   [The Progestin in HRT lowers the risk of uterine cancer.]   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 (Wikipedia).  Synthetic plant and horse estrogens are inferior to evolved human hormones.  The synthetics progestin MPA in Prempro is much worse than progesterone.  As for other synthetic progestins, little is known about their side effects.  What follows are 3 sections:  setting the record straight by comparing natural HRT to Prempro; then a list of HRT’s benefits supported by links to articles; last are recommendations.     

^^^^^^^ Setting the record straight Prempro & natural HRT --  for more  http://healthfully.org/fhr/  ^^^^^^^ 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 ) completed in 1998  used Prempro; moreover, the medical literature had numerous disappointing results for Prempro when compared to natural HRT formulas.  Prempro consists of an estrogen cocktail derived from pregnant mare’s urine to which is added the synthetic progestogen MPA.  (The tragic treatment and slaughter produced from collecting urine for estrogen 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%.   (Compare this to the benefits of using the natural estradiol with progesterone listed at the top of the first page.)  The press made the most of the WHI results (undoubtedly with a nod from their biggest advertiser[3]). HRT sales plummeted with this assault.  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) and still first in sales (more proof that corporations dominate medical information).   Based on the WHI, NIH issued this warning: “…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 and risks for the individual woman”.  The warning is placed on all packages of HRT, and it is accepted as correct by most doctors.  I suspected the worst of NIH and PhARMA having followed in the journals HRT and the birth control pill since the early 70s.  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 results can only be validly applied to Prempro.  Over 50 years of research was not overturned; but physicians and the public were tragically misled by the press, PhARMA, and the NIH. 

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…. [MPA] has 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….  Neuroendocrinologist Bruce S. McEwen 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 increased breast cancer]." In addition, 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.  ------BENEFITS:  Cardiovascular disease (CVD) with estrogen lowered by 20% cholesterol, 37% LDL (bad cholesterol) and raised by 14% HDL 14%, extends life 2.1 years, Braunwald, Heart Disease …, 5^th Ed, 1997, p 1708 tables.  “Estrogen-replacement therapy decreases CAD morbidity and CAD mortality …. In a meta-analysis … the relative risk for CAD in postmenopausal subjects… was 0.56 compared to subjects not taking estrogen” [a 44% reduction] Braunwald supra 1142.  Another study found a 50% reduction in CHD.  This is because estradiol blocks oxidation of LDL.  Estradiol completely reverses the effects induced by oxLDL on the DDAH/ADMA/NO pathway, thus avoid MPA and LNG (levonorgestrel).  Another study found 26 deaths vs. 56 for placebo.  A meta-study found and a 50% reduction of Coronary Heart Disease.  High cholesterol increase risk, but it is oxidative damage to LDL that causes of CVD.

Decreases breast cancer 73% using 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.”  “MPA increases the risk of breast cancer” (what PhARMA uses to attach all HRT).  Other progestins, especially MPA, increase risk.  Contrary to PhARMA’s thought leaders, estradiol reduces risk, and for breast cancer survivors, those who received HRT had at 15 years after cancer 300% greater survival than those who didn’t.    

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.” 

Alzheimer’s disease reduced 83% with  long-term HRT.  This is because estrogen is neuro-protective, it inhibits oxidative damage.  Progesterone also limits damage; thus is used in large doses following trauma “to limit central nervous system damage.”

Thrombosis:  an 8% reduction in risk of with Esterfied Estrogen while those on Prempro had a 65% elevated risk JAMA 04,  “Cases and controls, whose average age was 65 years, did not differ significantly on matching variables or on current use of exogenous estrogen (5.1% of cases versus 6.3% of controls).”  A 23% reduction with estrogen is significant!

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

Healthier skin American Journal of Clinical Dermatology, “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 hormone replacement therapy.” The mean collagen content in the skin was found to be 48% greater.   Conclusions: HRT improved skin ageing.

Osteoporosis:   “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”   Bone gain from long-term HRT; estradiol's role. 

Rheumatoid Arthritis (RA):  “Transdermal 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 RA.”

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

Macular degeneration, age related. HRT resulted in a 36% reduction and other eye pathologies.   

Sexual Satisfaction: “HRT improves sexual function in the orgasm, lubrication and pain domains …”

Mood elevation and depression: “Numerous molecular and clinical studies have implicated estrogen in modulating brain function including that related to mood,” and for treatment of mood disorders and depression.

10 Reasons for HRT:  Menopause Int.  & Oncology.  Both list the above benefits, and the latter advices HRT for breast cancer patient survivor that they take HRT because of “a 70% reduction in the risk of death” during the 15 years.

Sarcopenia refers to the loss of skeletal muscle mass with age and is associated with low level of estrogen or TTT (testosterone).   Sarcopenia in 22.6% in older postmenopausal women not receiving estrogen or TTT.   TTT