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History of Hormone Replacement

The Rise & Fall of Natural Hormones

Steroid chemists often refer to the 1930s as the Decade of the Sex Hormones, when the molecular structures of certain sex hormones were determined and first introduced to medical practice as drugs. Russell Marker achieved the first practical synthesis of the pregnancy hormone, progesterone, by what now is known as the “Marker Degradation.” Produced from starting material in a species of Mexican yam, Marker’s progesterone eventually became the preferred precursor in the industrial preparation of the anti-inflammatory drug cortisone. Important research on sex hormones continued in Mexico, leading to the synthesis of the first useful oral contraceptive in 1951.

Click Here To Learn More About Russell Marker And The Mexican Steroid Hormone Industry


In the 1960’s, doctor’s began prescribing estrogen therapy to women and millions began using pregnant horse-derived estrogens, Premarin – collectively known as conjugated equine estrogens (CEE). Premarin includes estrone sulfate, the primary active component in conjugated estrogen, constituting roughly 50-70% of the total content. It is worth noting that excess estrone is associated with higher rates of heart attacks, strokes, and breast cancer.


The Kaiser Study

In 1977, studies done at Kaiser Permanente Hospital in San Francisco showed that women taking Premarin had a rate of endometrial cancer five-fold higher than that of non-users.

To counteract the harmful effects of the Premarin being prescribed to women, doctors began prescribing the synthetic progesterone (progestin), Provera (MPA), along with Premarin. This chemical was not the same natural hormone progesterone that Russell Marker was able to make. It was a drug with hormone like effects; it did not fit in the receptor properly. In addition, it increased the risk of stroke in post-menopausal women.

Read more about the Kaiser Study


The E3N Cohort Study

This large study in 1990 looked at 80,377 women aged 40-65 (the youngest women to date) and found that when natural estradiol was given with natural bioidentical progesterone, there was NO increased risk of breast cancer. However, when synthetic progesterone was used, the risk of breast cancer increased by 69%! It even found that short spells of synthetic progesterone usage increased risk of breast cancer by 36%.

Read more about The French E3N Cohort Study


The Postmenopausal Estrogen-Progestin Intervention (PEPI)

In 1996, this trial took place over a four-year period using 875 healthy postmenopausal women aged 45 to 64 (includes the youngest group to date) as test subjects. It revealed that women taking estrogens from pregnant horses, Premarin, and either the natural hormone Progesterone or its synthetic version, Provera, had less chance of endometrial cancer but a higher risk of inflammation leading to cardiac events.

Read more about The PEPI Study


The Heart and Estrogen-Progestin Replacement Study (HERS)

In 1998,In 1998, the trial began in 1998 with a trial group of 2763 women. It was found that women taking Prempro, a combination drug containing estrogens from pregnant horses, along with the synthetic progesterone, Provera, had a 4-5X increased risk of breast cancer with 5-10 year of use, increases blood clots, and a 50% increase of heart disease the first year.

To this day, the reason for the increase in breast cancer is still unknown, but the general consensus was it was the PROVERA!

Read more about The HERS Study


The Women’s Health Initiative (WHI)

In 2002, this trial was one of the largest prevention studies done in the US — with more than 160, 000 women over 15 years. It further reported on the use of daily conjugated estrogens from pregnant horses combined with a progestin, not progesterone. It found that women taking these chemicals were at a higher risk for heart disease, stroke and breast cancer after 5 years. However, the estrogen only arm in women with a hysterectomy resulted in 21% less breast cancer.

This study led to millions of women avoiding hormone therapy, and many new menopausal women never starting hormone therapy.

The real problem with this study: it led to mass confusion in the medical community, and unfortunately natural bioidentical estrogen and progesterone were mistakenly thrown into the same category as horse-derived estrogen and synthetic progesterone!

Read more about The WHI Study


The Danish Study

In 2008, according to the European Society of Cardiology, “The study is the largest to look at the effects of HRT since the Women’s Health Initiative trial was stopped early after finding that HRT increased the risk of women developing a range of conditions including breast cancer and thromboembolism.
The research is an observational study of 698,098 healthy Danish women, aged 51-69, who were followed between 1995-2001. It has found that overall there was no increased risk of heart attacks in current users of HRT compared to women who had never taken it.

The study also found that the type of HRT and the way that the women took it made a difference to the risk of heart attacks. Continuous HRT (a continuous combination of oestrogen and progesterone) carried a 35% increased risk of heart attacks compared with women who had never used HRT. But if HRT was taken on a cyclical basis (oestrogen, followed by a combination of oestrogen and progesterone) there was a tendency for these women to have a reduced risk of heart attacks compared to women who had never used HRT, and this was also seen if a synthetic hormone, tibolone, was used. It also found that if used early, and even for longer than 10 years, these did not result in an increased risk for breast cancer.

This may be a clue!

Read more about Danish Study


The Kronos Early Estrogen Prevention Study (KEEPS)

In 2013, consisting of 727 women aged 42-59 found that low doses of natural estradiol cycled with natural progesterone for 12 days of each month within 3 years after menopause improved blood glucose control, Improved Insulin sensitivity, did not increase rates of breast cancer, endometrial cancer, stroke, or venous thrombosis.

Read more about Kronos Early Estrogen Prevention Study


Vascular Effects of Early versus Late Postmenopausal Treatment with Estradiol (ELITE Study)

Does timing matter?

Data suggest that estrogen-containing hormone therapy is associated with beneficial effects with regard to cardiovascular disease when the therapy is initiated temporally close to menopause but not when it is initiated later.
A total of 643 postmenopausal women were randomized according to their number of years since menopause, less than 6 years or 10 years or more, to receive either oral estradiol daily or a placebo plus progesterone vaginal gel administered sequentially (for women with a uterus) or placebo. The primary outcome was the rate of change in carotid-artery intima–media thickness (CIMT), which was measured every 6 months. Secondary outcomes included an assessment of coronary atherosclerosis by cardiac computed tomography (CT), which was performed when participants completed the randomly assigned regimen.

It concluded, oral estradiol therapy was associated with less progression of subclinical atherosclerosis (measured as CIMT) than was placebo when therapy was initiated within 6 years after menopause but not when it was initiated 10 or more years after menopause.

Read more about the ELITE Study


  • Most of the studies used synthetic hormones continuously combined and had some type of negative result.

The positive results:

  • The Danish Study showed a decreased risk of myocardial infarction and was based on a cyclic-combined, transdermal regimen resulting in a monthly bleed.

  • The E3N Cohort Study – was unique for its 40-65 year old age span. It used natural estradiol and natural bioidentical progesterone. There was no increased risk of breast cancer as compared to the use of synthetic progesterone.

  • KEEPS found that low doses of estradiol cycled with natural progesterone, within three years after menopause improved blood glucose control, insulin sensitivity, and did not increase rates of breast cancer, endometrial cancer, stroke or venous thrombosis.

WHN Conclusions:

  1. Use natural bioidentical hormones.
  2. Always use natural bioidentical estrogen cycled with natural bioidentical progesterone.
  3. Use estrogen and progesterone early during peri-menopause to prevent symptoms and decrease mortality, myocardial infarction and heart failure rates.
  4. Evidence may support taking bioidentical estrogens for more than 10 years
  5. Evidence supports that cyclical bioidentical estrogen and progesterone do not cause cancer.