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I borrowed this from the Hormone Foundation
Evolution of Estrogen
1889
Charles Edouard Brown-Sequard, one of the first to be interested in replacement hormones and considered by some to be the father of endocrinology, reports
reversal of his own symptoms of aging by the intravenous administration of
testicular extracts. He suggests that ovarian extracts would have the same effect in women (1).
1897
The first report stating that ovarian extracts can be used to relieve postmenopausal vasomotor symptoms is issued (1).
1900
The life expectancy of American women is approximately 45 years (2).
Soules et al. J Am Geriatr Soc. 1982;30:548
1906
F. Marshall and W. Jolly in England are the first to recognize that ovaries produce two substances, which are responsible for menstruation and implantation. They would later be called estrogen and progesterone (3).
1919
Ludwig Haberlandt, an Austrian physiologist, provides the first hint that an oral contraceptive (OC) is possible when he renders female deer infertile by injecting subcutaneous implants of ovaries from pregnant rabbits. Eight years later he achieves temporary sterility in mice with the oral administration of ovarian extracts (4).
1929
E. Doisy in St. Louis and Adolf Butenandt in Germany isolate, from human pregnancy urine, the estrus-producing substance in its crystalline form. Both conclude it was a hydroxyketone whose formula was C18H22O2 (estrone) (5,6).
Estrone
The first American attempt to treat menopausal symptoms is attributed to E. L. Severinghaus and J. Evans, who administer a derivative from the amniotic fluid of cattle (1).
1930
Because estrone and estriol are not water-soluble, they are mixed with oil and given in a subcutaneous manner to have a clinical effect. The oral administration is not feasible since the estrogenic activity of oral estrone falls to 1/200 of the subcutaneous form.
Bernhard Zondek in Germany discovers that the urine of horses contains water-soluble estrogens. Guy Marrian in London finds a water-soluble estrogen in pregnancy urine, which is different from estrone. He finds that by letting the urine decompose, its estrogenic activity increases. This compound is later identified as estriol glucuronide, the activity of which increases after hydrolysis to form estradiol.
Estradiol
James B. Collip of McGill University obtains Emmenin® from the urine of pregnant women. Emmenin, consisting of water-soluble estrogens, is the first replacement product to contain conjugated estrogens (7) and is marketed in the U.S. in 1933. Emmenin, containing estriol glucuronide, exhibits one-third of the estrogenic activity of the subcutaneous route when given orally.
1934
Guy Marrian and Desmond Beale at the University of Toronto publish a method for the large-scale production of estrone from pregnant mares' urine (PMU) (8).
1937
Establishing the physiologic basis for hormone contraception, Makepeace, Wienstein and Friedman, at the University of Pennsylvania, prevent ovulation in a rabbit with progesterone (9). The search begins for an orally active progestin with a long duration of action and high potency. Progesterone, inactive at this time when taken orally, provides the basic structure for modification to create highly potent oral progestins.
Ethisterone 1937
19-norprogesterone 1944
Norethindrone 1951
Norethynodrel 1951
1939
Because of difficulties in production, Emmenin cannot be made quickly enough to keep up with consumer demand. A more practical source for potent estrogens is needed. Ayerst discovers that PMU contains large quantities of orally active, water-soluble estrogen conjugates.
Diethylstilbestrol (DES) is marketed as a more potent estrogen than Emmenin.
1942
Premarin® 1.25 mg is introduced into the U.S. market. The lower doses of Premarin - 0.625 mg and 0.3 mg - are introduced in 1948.
1946
George and Olive Smith tout the therapeutic value of DES for the prevention of pregnancy complications, such as toxemia, low birth weight and early pregnancy loss. It is estimated that approximately two million women are exposed to DES during pregnancy (9). About five years later, W.J. Sieckmann and M.E. Davis in Chicago conduct the first controlled trial with DES that shows no clinical benefit in preventing complications during pregnancy (10).
1950s
Ayerst institutes a massive education program for physicians that focuses on menopause, menopausal symptoms and the consequences of estrogen loss. Premarin is thought to contain only 10 estrogens.
1956
Gregory Pincus and John Rock, with a grant from Planned Parenthood Founder Margaret Sanger, conduct the first controlled trial with a contraceptive pill containing norethynodrel. There are no pregnancies reported in 1,279 cycles (9).
1957
Enovid®‚ the norethynodrel-containing OC, is approved and marketed only for the treatment of menstrual disturbances.
1960s
Estrogen replacement therapy (ERT) use surges. About 12% of all postmenopausal women use ERT. Premarin use grows 170% from 1963 to 1966 and becomes the #1 dispensed drug in America. The most prescribed doses of Premarin are 1.25 mg and 2.5 mg (11).
1960
On May 9, 1960, the U.S. FDA announces its approval of Enovid, the first OC marketed for the prevention of pregnancy.
1964
The first ethinyl estradiol OC pill is introduced into the U.S. market. Within a year there are more than 2.3 million OC users (9).
1968
Reports link the use of high-dose OCs to an increased risk of cardiovascular disease (12,13,14).
Early 1970s
Studies show a lower risk of cardiovascular disease with OCs containing less than 50 mcg ethinyl estradiol compared to those containing more than 50 mcg ethinyl estradiol (15,16,17). High-dose OC use begins to decline, while the number of prescriptions for lower-dose pills increases.
1975
Studies reveal an increased incidence of endometrial cancer among women using unopposed estrogens (18,19).
1976
The Nurses' Health Study is initiated with 121,700 registered nurses, 30-55 years of age, to evaluate the effects of menopausal estrogen use on cardiovascular disease, cancers, mortality and other disease processes.
1977
A registry is formed to collect information regarding the use of DES, the subsequent development of genital tract lesions in newborns, and gynecologic cancers in young women exposed to the drug in utero. The FDA states, "there is no proper use of estrogen in pregnant women" (9).
1980
Weiss shows a 60 percent reduced risk of hip and wrist fractures in women taking ERT (20).
Early
1980s
Studies show that the risk of endometrial cancer in women who have a uterus and take estrogen replacement can be reduced below that of nonusers by adding a cyclic or continuous progestin to their treatment (21,22,23,24).
The first published epidemiologic reports of reduced cardiovascular risk with the use of postmenopausal estrogen begin to appear (25,26,27).
Robert Lindsay reports results from a controlled trial showing that doses of Premarin as low as 0.625 mg inhibit postmenopausal bone loss (28).
Late 1980s
Transdermal estrogens are introduced into the U.S. market.
Premarin receives a prevention of osteoporosis indication. Postmenopausal estrogen use increases. Premarin 0.625 mg becomes the most commonly prescribed dose (29).
Multiple observational studies evaluating the effect of postmenopausal estrogens and the potential increased risk of breast cancer are reported with no definitive conclusions.
Studies demonstrate the noncontraceptive health benefits of OCs (30).
Early 1990s
Multiple epidemiological studies show a 40-50 percent reduction in cardiovascular disease in women using postmenopausal estrogens (31).
Studies demonstrate the presence of multiple estrogenic components in Premarin (32).
Tamoxifen is the first selective estrogen receptor modulator (SERM) introduced for use in the treatment of women with breast cancer (33).
An increasing interest in alternative medicine develops in the United States even though controlled clinical studies do not show clinical improvements with most of these alternatives. For example, dong quai and placebo have a similar effect on menopausal symptom (34). Use of phytoestrogens for the treatment of menopausal symptoms increases (35).
Commonly Used Alternatives to Hormone Replacement Therapy
- Black Cohash
- Camomile
- Chasteberry
- Dong Quai
- Ginseng
- Licorice Root
- St. John's Wort
- Valerian
- Soy Products
OCs contain one-fourth the estrogen and one-tenth the progestin dose of earlier pills.
The Women's Health Initiative (WHI) clinical trial and observational study, sponsored by the National Institutes of Health, is initiated with a planned completion date of 2007. More than 161,000 postmenopausal women, ranging in age from 50-79, are enrolled at one of 40 WHI clinical centers nationwide, with more than 27,000 randomized to hormone therapy. The objective of the clinical trial is to evaluate the effects of postmenopausal estrogen use, dietary patterns and calcium/vitamin D supplements on overall mortality, cardiovascular disease, breast cancer, colon cancer, osteoporosis and other disease processes.
Mid 1990s
Studies suggest an increased incidence of endometrial cancer with long-term tamoxifen use (36).
Studies suggest postmenopausal estrogen use may play a role in the prevention of the following diseases: Alzheimer's disease, age-related eye disease, colon cancer and tooth loss (37,38,39,40).
Initiation of the Women's Health, Osteoporosis, Progestin, Estrogen Study (Women's HOPE Study) to evaluate the effects of low-dose HRT on menopausal symptoms and osteoporosis. The Women's HOPE Study is the first large trial to evaluate the effects of low-dose therapy on menopausal symptoms, amenorrhea, osteoporosis and metabolism.
The Postmenopausal Estrogen/Progestin Interventions (PEPI) trial shows that Premarin 0.625 mg, with or without a progestin, results in increases in bone mineral density in both the hip and spine (41).
Late 1990s
Studies suggest that estrogens may protect women against diabetes and Parkinson's disease (42, 43).
Estrogen receptors are identified in multiple organ systems.
Multiple mechanisms to explain the possible beneficial effects of estrogens in organ systems, such as the cardiovascular system, begin to be delineated.
A second estrogen receptor is discovered. The two estrogen receptors (alpha and beta) are distributed differently throughout the body.
New clinical trials begin in the hopes of identifying the ideal SERM. Raloxifene, a second generation SERM, is introduced for the prevention of osteoporosis. The Multiple Outcomes of Raloxifene Evaluation (MORE) and the Raloxifene Use for The Heart (RUTH) trials are initiated to determine the effect of raloxifene on bone health as well as the incidence of breast cancer and cardiovascular disease (44,45,46).
In addition to providing effective contraception, low-dose OCs are shown to reduce menopausal symptoms by half and improve quality of life for perimenopausal women (47).
1997
A re-analysis of the data from 51 epidemiological studies suggests an increased risk of breast cancer with postmenopausal estrogen use (48). The debate regarding the effect of estrogens continues, awaiting results from prospective randomized trials.
*P=.009, for trend-time analysis
Hulley et al. JAMA. 1998;280:605
1998
The Heart Estrogen/Progestin Replacement Study (HERS) concludes, unable to demonstrate a cardiovascular benefit of HRT in postmenopausal women with established coronary artery disease (49). Women given HRT show an increased risk of a second cardiovascular event during the first year compared to women given placebo. A time-trend analysis shows improvement with HRT over time.
Evolution of Estrogen
1889
Charles Edouard Brown-Sequard, one of the first to be interested in replacement hormones and considered by some to be the father of endocrinology, reports
reversal of his own symptoms of aging by the intravenous administration of
testicular extracts. He suggests that ovarian extracts would have the same effect in women (1).
1897
The first report stating that ovarian extracts can be used to relieve postmenopausal vasomotor symptoms is issued (1).
1900
The life expectancy of American women is approximately 45 years (2).
Soules et al. J Am Geriatr Soc. 1982;30:548
1906
F. Marshall and W. Jolly in England are the first to recognize that ovaries produce two substances, which are responsible for menstruation and implantation. They would later be called estrogen and progesterone (3).
1919
Ludwig Haberlandt, an Austrian physiologist, provides the first hint that an oral contraceptive (OC) is possible when he renders female deer infertile by injecting subcutaneous implants of ovaries from pregnant rabbits. Eight years later he achieves temporary sterility in mice with the oral administration of ovarian extracts (4).
1929
E. Doisy in St. Louis and Adolf Butenandt in Germany isolate, from human pregnancy urine, the estrus-producing substance in its crystalline form. Both conclude it was a hydroxyketone whose formula was C18H22O2 (estrone) (5,6).
Estrone The first American attempt to treat menopausal symptoms is attributed to E. L. Severinghaus and J. Evans, who administer a derivative from the amniotic fluid of cattle (1).
1930
Because estrone and estriol are not water-soluble, they are mixed with oil and given in a subcutaneous manner to have a clinical effect. The oral administration is not feasible since the estrogenic activity of oral estrone falls to 1/200 of the subcutaneous form.
Bernhard Zondek in Germany discovers that the urine of horses contains water-soluble estrogens. Guy Marrian in London finds a water-soluble estrogen in pregnancy urine, which is different from estrone. He finds that by letting the urine decompose, its estrogenic activity increases. This compound is later identified as estriol glucuronide, the activity of which increases after hydrolysis to form estradiol.
Estradiol James B. Collip of McGill University obtains Emmenin® from the urine of pregnant women. Emmenin, consisting of water-soluble estrogens, is the first replacement product to contain conjugated estrogens (7) and is marketed in the U.S. in 1933. Emmenin, containing estriol glucuronide, exhibits one-third of the estrogenic activity of the subcutaneous route when given orally.
1934
Guy Marrian and Desmond Beale at the University of Toronto publish a method for the large-scale production of estrone from pregnant mares' urine (PMU) (8).
1937
Establishing the physiologic basis for hormone contraception, Makepeace, Wienstein and Friedman, at the University of Pennsylvania, prevent ovulation in a rabbit with progesterone (9). The search begins for an orally active progestin with a long duration of action and high potency. Progesterone, inactive at this time when taken orally, provides the basic structure for modification to create highly potent oral progestins.
Ethisterone 1937
19-norprogesterone 1944
Norethindrone 1951
Norethynodrel 1951
1939
Because of difficulties in production, Emmenin cannot be made quickly enough to keep up with consumer demand. A more practical source for potent estrogens is needed. Ayerst discovers that PMU contains large quantities of orally active, water-soluble estrogen conjugates.
Diethylstilbestrol (DES) is marketed as a more potent estrogen than Emmenin.
1942
Premarin® 1.25 mg is introduced into the U.S. market. The lower doses of Premarin - 0.625 mg and 0.3 mg - are introduced in 1948.
1946
George and Olive Smith tout the therapeutic value of DES for the prevention of pregnancy complications, such as toxemia, low birth weight and early pregnancy loss. It is estimated that approximately two million women are exposed to DES during pregnancy (9). About five years later, W.J. Sieckmann and M.E. Davis in Chicago conduct the first controlled trial with DES that shows no clinical benefit in preventing complications during pregnancy (10).
1950s
Ayerst institutes a massive education program for physicians that focuses on menopause, menopausal symptoms and the consequences of estrogen loss. Premarin is thought to contain only 10 estrogens.
1956
Gregory Pincus and John Rock, with a grant from Planned Parenthood Founder Margaret Sanger, conduct the first controlled trial with a contraceptive pill containing norethynodrel. There are no pregnancies reported in 1,279 cycles (9).
1957
Enovid®‚ the norethynodrel-containing OC, is approved and marketed only for the treatment of menstrual disturbances.
1960s
Estrogen replacement therapy (ERT) use surges. About 12% of all postmenopausal women use ERT. Premarin use grows 170% from 1963 to 1966 and becomes the #1 dispensed drug in America. The most prescribed doses of Premarin are 1.25 mg and 2.5 mg (11).
1960
On May 9, 1960, the U.S. FDA announces its approval of Enovid, the first OC marketed for the prevention of pregnancy.
1964
The first ethinyl estradiol OC pill is introduced into the U.S. market. Within a year there are more than 2.3 million OC users (9).
1968
Reports link the use of high-dose OCs to an increased risk of cardiovascular disease (12,13,14).
Early 1970s
Studies show a lower risk of cardiovascular disease with OCs containing less than 50 mcg ethinyl estradiol compared to those containing more than 50 mcg ethinyl estradiol (15,16,17). High-dose OC use begins to decline, while the number of prescriptions for lower-dose pills increases.
1975
Studies reveal an increased incidence of endometrial cancer among women using unopposed estrogens (18,19).
1976
The Nurses' Health Study is initiated with 121,700 registered nurses, 30-55 years of age, to evaluate the effects of menopausal estrogen use on cardiovascular disease, cancers, mortality and other disease processes.
1977
A registry is formed to collect information regarding the use of DES, the subsequent development of genital tract lesions in newborns, and gynecologic cancers in young women exposed to the drug in utero. The FDA states, "there is no proper use of estrogen in pregnant women" (9).
1980
Weiss shows a 60 percent reduced risk of hip and wrist fractures in women taking ERT (20).
Early
1980s
Studies show that the risk of endometrial cancer in women who have a uterus and take estrogen replacement can be reduced below that of nonusers by adding a cyclic or continuous progestin to their treatment (21,22,23,24).
The first published epidemiologic reports of reduced cardiovascular risk with the use of postmenopausal estrogen begin to appear (25,26,27).
Robert Lindsay reports results from a controlled trial showing that doses of Premarin as low as 0.625 mg inhibit postmenopausal bone loss (28).
Late 1980s
Transdermal estrogens are introduced into the U.S. market.
Premarin receives a prevention of osteoporosis indication. Postmenopausal estrogen use increases. Premarin 0.625 mg becomes the most commonly prescribed dose (29).
Multiple observational studies evaluating the effect of postmenopausal estrogens and the potential increased risk of breast cancer are reported with no definitive conclusions.
Studies demonstrate the noncontraceptive health benefits of OCs (30).
Early 1990s
Multiple epidemiological studies show a 40-50 percent reduction in cardiovascular disease in women using postmenopausal estrogens (31).
Studies demonstrate the presence of multiple estrogenic components in Premarin (32).
Tamoxifen is the first selective estrogen receptor modulator (SERM) introduced for use in the treatment of women with breast cancer (33).
An increasing interest in alternative medicine develops in the United States even though controlled clinical studies do not show clinical improvements with most of these alternatives. For example, dong quai and placebo have a similar effect on menopausal symptom (34). Use of phytoestrogens for the treatment of menopausal symptoms increases (35).
Commonly Used Alternatives to Hormone Replacement Therapy
- Black Cohash
- Camomile
- Chasteberry
- Dong Quai
- Ginseng
- Licorice Root
- St. John's Wort
- Valerian
- Soy Products
OCs contain one-fourth the estrogen and one-tenth the progestin dose of earlier pills.
The Women's Health Initiative (WHI) clinical trial and observational study, sponsored by the National Institutes of Health, is initiated with a planned completion date of 2007. More than 161,000 postmenopausal women, ranging in age from 50-79, are enrolled at one of 40 WHI clinical centers nationwide, with more than 27,000 randomized to hormone therapy. The objective of the clinical trial is to evaluate the effects of postmenopausal estrogen use, dietary patterns and calcium/vitamin D supplements on overall mortality, cardiovascular disease, breast cancer, colon cancer, osteoporosis and other disease processes.
Mid 1990s
Studies suggest an increased incidence of endometrial cancer with long-term tamoxifen use (36).
Studies suggest postmenopausal estrogen use may play a role in the prevention of the following diseases: Alzheimer's disease, age-related eye disease, colon cancer and tooth loss (37,38,39,40).
Initiation of the Women's Health, Osteoporosis, Progestin, Estrogen Study (Women's HOPE Study) to evaluate the effects of low-dose HRT on menopausal symptoms and osteoporosis. The Women's HOPE Study is the first large trial to evaluate the effects of low-dose therapy on menopausal symptoms, amenorrhea, osteoporosis and metabolism.
The Postmenopausal Estrogen/Progestin Interventions (PEPI) trial shows that Premarin 0.625 mg, with or without a progestin, results in increases in bone mineral density in both the hip and spine (41).
Late 1990s
Studies suggest that estrogens may protect women against diabetes and Parkinson's disease (42, 43).
Estrogen receptors are identified in multiple organ systems.
Multiple mechanisms to explain the possible beneficial effects of estrogens in organ systems, such as the cardiovascular system, begin to be delineated.
A second estrogen receptor is discovered. The two estrogen receptors (alpha and beta) are distributed differently throughout the body.
New clinical trials begin in the hopes of identifying the ideal SERM. Raloxifene, a second generation SERM, is introduced for the prevention of osteoporosis. The Multiple Outcomes of Raloxifene Evaluation (MORE) and the Raloxifene Use for The Heart (RUTH) trials are initiated to determine the effect of raloxifene on bone health as well as the incidence of breast cancer and cardiovascular disease (44,45,46).
In addition to providing effective contraception, low-dose OCs are shown to reduce menopausal symptoms by half and improve quality of life for perimenopausal women (47).
1997
A re-analysis of the data from 51 epidemiological studies suggests an increased risk of breast cancer with postmenopausal estrogen use (48). The debate regarding the effect of estrogens continues, awaiting results from prospective randomized trials.
*P=.009, for trend-time analysis
Hulley et al. JAMA. 1998;280:605
1998
The Heart Estrogen/Progestin Replacement Study (HERS) concludes, unable to demonstrate a cardiovascular benefit of HRT in postmenopausal women with established coronary artery disease (49). Women given HRT show an increased risk of a second cardiovascular event during the first year compared to women given placebo. A time-trend analysis shows improvement with HRT over time.
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