Some background information assembled by jk

It makes all the difference for the earlier studies were before Big PhARMA made a concerted effort to change the prescribing practices and public’s opinion.   

Why equine estrogen.  The first major source of estrogen was from Ayerst Laborites; called Emmenin was derived from late-pregnancy urine of Canadian women, and was introduced in 1930 as the first orally effective estrogen.  The next source was from Stallions, but they frequently kicked over their collection buckets.  Mares, in contrast, provided a much better collection source, and their urine was approximately 2.5 times as potent as human urine.    Ayerst called the product Premarin, a label still applied to equine estrogen.  A similar course of events followed in Germany with Schering, starting in 1938.  Also at Schering in 1938 Inhoffen & Hohlweg synthesized ethinyl estradiol, which is still used in birth control and HRT.   Also in 1938 a team of English chemist led by Dodds developed a cheap, nonsteroidal estrogen, diethylstilbestrol (DES), which had similar effects at 1/3^rd the concentration.   Following British custom for scientists, the procedure was published in Nature, thus Dodds relinquished patent right.  In 1938 patented ethinyl estradiol cost $300 per gram, and DES $2 per gram (multiply by 30 to convert to the current dollar).  Equine estrogen however over time succeed in dominating the market. Thus Wyeth’s Premarin became the number one prescribe drug in the U.S. in 1992, and in 1997 sales reached $1 billion.  DES also used to prevent miscarriages was shown in 1971 to be linked to vaginal cancer of daughters of users.  It was removed from the market in 1975 by the FDA. 

There is a 90% drop in the estrogen and progesterone levels following menopause.   However, women on HRT, have a youthful estrogen level.  With estrogen alone there were observed uterine changes in women on HRT, and for a decade it was suspected to increase the risk of uterine cancer.  This was confirmed and in 1975.  One study found a 5 fold risk increase in this uncommon cancer.  This hazard was reversed with the introduction of progesterone or a progestin.   By 1988 most HRT prescriptions contained them for women with an intact uterus.  

In 1986 the FDA announced that it approved estrogen as an effective treatment of postmenopausal osteoporosis, which reversed their 1976 finding. 

Unfortunately there was and still is a general failure to distinguish between equine estrogen, and other forms estrogen, and between progesterone and progestin MPA in Provera.  This has muddled the issue of risk reward.   Various major health concern (heart attacks, breast cancer and thrombosis) are increased with Proprem, a combination of equine estrogen and progestin MPA.  The opposite is true with Esterifed Estrogen and progesterone.  They reduce the risk of heart attack 32%, coronary heart disease 50%, Alzheimer’s 83%, and osteoporosis 90%.  Only a few studies distinguish which drugs are used thus mixing the effective with the ineffective or using Prempro alone.   Unfortunately Proprem is still the leading HRT. 

Ethynyl estradiol (EE is a derivative of estradiol is an orally bio-active formulation of estrogen that is used in almost all modern formulations of combined oral contraceptive pills.  While estradiol is readily absorbed when taken orally, it is also quickly inactivated by the liver. Substitution at C17 of the estrane steroid with an ethinyl group proved to provide an estrogen that is much more resistant to degradation and paved the way for the development of oral contraceptives.

Without HRT, women loose bone density, thus no change is a very positive finding--jk.

Esterified estrogen therapy in postmenopausal women. Relationships of bone marker changes and plasma estradiol to BMD changes: A two-year study

Abstract

Objective: To determine the relationships among bone mineral density changes, bone marker changes, and plasma estrogens in postmenopausal women receiving estrogen replacement therapy.

Design: A total of 406 postmenopausal women received 1,000 mg calcium and continuous esterified estrogens (0.3 mg, 0.625 mg, or 1.25 mg) or placebo daily for up to 24 months. Bone mineral density and bone marker measurements were determined at 6-month intervals; plasma estrogens were measured in a subset after 12, 18, and 24 months.

Results: Esterified estrogens produced significant increases in bone mineral density (lumbar spine, hip) compared with baseline and placebo at 6, 12, 18, and 24 months. Bone markers decreased from baseline with all esterified estrogen doses relative to placebo. Bone marker changes at 6 months correlated negatively with bone mineral density changes at 24 months (correlation coefficient range = -0.122 to -0.439). The strongest correlation was noted for spine bone mineral density changes and serum osteocalcin. Mean plasma estrogen levels increased with esterified estrogen dose, and bone mineral density changes correlated positively with plasma estrogen levels. Positive bone mineral density changes were noted in treatment groups with plasma estradiol levels at and above 25 pg/mL.

Conclusions: Esterified estrogens, at doses from 0.3 mg to 1.25 mg/day, unopposed by progestin, increase bone mineral density of the spine and hip in postmenopausal women. These bone mineral density changes correlated significantly with bone marker changes at 6 months and with plasma estrogens at 12, 18, or 24 months. Data variability minimizes the predictive value of the bone marker changes in monitoring individual therapy.

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Low-Dose Esterified Estrogen Therapy

Effects on Bone, Plasma Estradiol Concentrations, Endometrium, and Lipid Levels

Arch Intern Med. 1997;157(22):2609-2615 at http://archinte.ama-assn.org/cgi/content/abstract/157/22/2609

The abstract didn’t list the form of estrogen.  Nor was the full article available on line--jk.

The American Journal of Medical Science

January 1997, Vol 313 Issue 1, pp 2-12

Abstract

Background
Prospective studies have shown that doses equivalent to conjugated equine estrogens of 0.625 mg/d or higher are needed to produce a significant increase in bone mineral density of the lumbar spine.

Objectives
To determine the effects of unopposed {without progesterone} esterified estrogens on bone mineral density, lipid levels, and endometrial tissue structure, and to relate these effects to changes in plasma estradiol levels.

Methods
Four hundred six postmenopausal women were given calcium, 1000 mg/d, and randomly assigned to receive continuous esterified estrogens (0.3, 0.625, or 1.25 mg/d) or placebo for 24 months. Bone mineral density measurements and endometrial and laboratory assessments were conducted every 6 months; plasma estradiol concentrations were measured after 12, 18, and 24 months.

Results
All doses of esterified estrogens produced significant increases in bone mineral density of the lumbar spine compared with baseline and with placebo at 6,12, 18, and 24 months. Mean plasma estradiol levels increased with esterified estrogens dose, and individual subject bone mineral density changes appeared related to plasma estradiol concentrations. Clinically relevant rates of endometrial hyperplasia were noted only in the groups receiving 0.625 and 1.25 mg of esterified estrogens daily. Lipid changes were dose related and apparent in all groups.

Conclusions
Esterified estrogens at doses from 0.3 to 1.25 mg/d, administered unopposed by progestin, produce a continuum of positive changes on bone and lipids. Plasma estradiol concentrations increased with esterified estrogens dose and were related to positive bone mineral densities. The 0.3-mg dose resulted in positive bone and lipid changes without inducing endometrial hyperplasia.

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Wikipedia.org on Osteoporosis

Exercise

Multiple studies have shown that aerobics, weight bearing, and resistance exercises can all maintain or increase BMD in postmenopausal women.^[71] Many researchers have attempted to pinpoint which types of exercise are most effective at improving BMD and other metrics of bone quality, however results have varied. The BEST (Bone-Estrogen Strength Training) Project at the University of Arizona identified six specific weight training exercises that yielded the largest improvements in BMD; this project suggests squat, military press, lat pull-down, leg press, back extension, and seated row, with three weight training sessions a week of two sets of each exercise, alternating between moderate (6-8 reps at 70% of 1-rep max) and heavy (4-6 reps at 80% of 1-rep max).^[72] One year of regular jumping exercises appears to increase the BMD and moment of inertia of the proximal tibia^[73] in normal postmenopausal women. Treadmill walking, gymnastic training, stepping, jumping, endurance, and strength exercises all resulted in significant increases of L2-L4 BMD in osteopenic postmenopausal women.^[74][75][76] Strength training elicited improvements specifically in distal radius and hip BMD.^[77] Exercise combined with other pharmacological treatments such as hormone replacement therapy (HRT) has been shown to increases BMD more than HRT alone.^[78]

Additional benefits for osteoporotic patients other than BMD increase include improvements in balance, gait, and a reduction in risk of falls.^[79]

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This Mayo Clinic article reveals the standard wisdom in treatment prior to the introduction of bisphosphonates.  Mayo Clinic recommendations carry significant authority--jk. 

Estrogen replacement therapy: current recommendations.

Mayo Clinic Proceedings, 1988 May; 63(5):  453-460 at http://www.ncbi.nlm.nih.gov/pubmed/3283471

Abstract

Estrogen replacement therapy is effective for the prevention and treatment of postmenopausal osteoporosis and should be offered to all women at high risk for osteoporosis. Such therapy is particularly beneficial for prevention of spinal compression fractures; in addition, it alleviates menopausal symptoms (hot flushes, genitourinary symptoms, and changes in mood). In each patient, these benefits must be weighted against the potential risks of endometrial hyperplasia and carcinoma, breast tenderness, hypertension, vascular headaches, and the inconvenience of menstrual bleeding if the uterus is intact. The risk of endometrial cancer associated with estrogen replacement therapy can be considerably reduced by the addition of a progestin, and other side effects can be diminished or eliminated by use of the new transdermal estrogen preparations. Thus, estrogen replacement therapy should be considered in all women who have experienced natural or surgically induced menopause, and it is advisable in women who have osteoporosis or an increased risk for this disorder and no contra-indications to its use. Estrogen replacement therapy should be instituted as soon after menopause as possible and seems to be well tolerated until at least 75 years of age.

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Obestetrics & Gynecology August 1990, Vol 76 Issue 2, at http://journals.lww.com/greenjournal/Abstract/1990/08000/Estrogen_Treatment_of_Patients_With_Established.29.aspx

Estrogen Treatment of Patients With Established Postmenopausal Osteoporosis*

Abstract

We conducted a controlled study of the effects of oral estrogen therapy in postmenopausal women with established postmenopausal osteoporosis. Bone mass was measured in the lumbar vertebrae and hip using dual photon absorptiometry. Both estrogen-treated women and the control group received calcium supplements to bring total intake to approximately 1500 mg? day. For those women with an intact uterus in the estrogen wing of the study, a progestin was added to the therapy for 12-14 days each calendar month. The number of years from menopause was 14.6 +/- 0.9 in the estrogen-treated group and 13.7 +/- 1.1 in the calcium-treated group. Estrogen treatment was associated with increased vertebral bone mass by dual photon absorptiometry during the 2 years of the study (+10.6%; P<.01). There was also an increase in bone density at the femoral neck (+5.5%; P<.1), but the difference from the initial value was not statistically significant. The group given calcium alone lost bone at both sites, although the loss was not statistically significant at either site. The response to estrogen was greatest in those who were furthest from menopause (r=0.38, P<.05) and consequently among those who had the lowest bone mass (r =- 0. 34, P<.05). Estrogen therapy appears to be an effective therapy for patients with established osteoporosis. Intervention is associated with a significant increase in bone mass compatible with reduced skeletal turnover and activation frequency.

(C) 1990 The American College of Obstetricians and Gynecologists

*  Though the full articles in this issue are available for free on line, this articles does not appear in the table of contents, and thus there is no link for the PDF version of the entire article.  The article below, in a different issue appears in both abstract and full PDF

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Estrogen Replacement Therapy I: A 10-Year Prospective Study in the Relationship to Osteoporosis

March 1979 Volume 53 Issue 3 at http://journals.lww.com/greenjournal/Abstract/1979/03000/Estrogen_Replacement_Therapy_I__A_10_Year.1.aspx

ABSTRACT

A 10-year, double-blind prospective study was undertaken to evaluate the effects of estrogen replacement therapy. The sample population consisted of 84 pairs of randomly chosen postmenopausal patients who were matched for age and diagnosis. One half of the patients received conjugated estrogens and cyclic progesterone, while the other half received placebo. Estrogen-treated patients whose therapy started within 3 years of menopause showed improvement or no increase in osteoporosis. Control patients demonstrate an increase in their osteoporosis.

(C) 1979 The American College of Obstetricians and Gynecologists

IMPORTANT POINTS TAKEN FROM ARTICLE BY jk.

Study began in 1965 using Prempro tablets (daily equine estrogen 2.5 mg and 10 medroxyprogesterone 7 days each month) by far the worst HRT for numerous reasons explained at length at http://healthfully.org/highinterestmedical/id3.html.  This dose was 2 to 4 times that presently (1979) recommended.  Currently .625 mg is the most common amount--jk. 

The women (84 pairs) were patients at Goldwater Memorial Hospital in New York City, a hospital for chronic diseases. 

At the end of the 10 year period, it was found that when HRT beings following menopause is relevant to outcome, and so two subgroups were formed those beginning HRT with 3 years and those more than 3 years from menopause; thus there were 4 groups, those on Prempro and the control groups.   The later therapy started the poorer the results, though for the control group the rate of bone loss remained nearly constant.  As noted, those who began later HRT from menopause faired much worse than those who began within 3 years.  The former had very modest loss of bone, while those who started within 3 years showed significant bone density gain.  There were 7 fractures in the control group and none in the treated group.  Among the treated group there were no new cases of osteoporosis but for the control group there were 6 cases (out of 84 patients). 

Since the late 1930s estrogen replacement therapy has been used to alleviate the problems of menopausal syndrome. In 1941 Albright Smith and Richardson reported the use of sex hormones as treatment for postmenopausal osteoporosis.  In the ensuing 30 years, estrogen has been the main therapy for this disease.  Androgens were frequently used in treatment until the introduction in the 1950s of synthetic analogs which had activity equal to that of testosterone, but markedly decreased virilizing properties.  Approximately 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 1 out of 6 of these women will die within 3 months of their injury.  By age 60, there are 10 times as many forearm fractures among women than among men.