In the late 1800s, knowledge of hormones was nonexistent. As a prelude to the discovery of other hormones, in the mid-1980s, Claude Bernard demonstrated that several glands produced internal secretions that could influence other distant organs in the body. In 1897, extracts from ovaries proved to be effective for the treatment of menopausal hot flashes. However, it was not until 1929 that Adolph Butenandt and Albert Doisy independently isolated and purified estrone, the first estrogen to be discovered. Subsequently, the other two forms of human estrogens, estradiol and estriol, were discovered.
Before estrogen hormone extraction processes for oral consumption were developed, the use of subcutaneous (under the skin) bio-identical hormone pellet therapy was first used in the mid-1930s. Even though bio-identical hormones were known to be effective and were available as early as the 1930s, the only way to avert their destruction by the digestive tract was to administer them intramuscularly in an oil-based injection. Since it was unlawful for pharmaceutical companies to patent natural substances and the technology was not yet available that would allow bio-identical hormones to be absorbed orally, researchers began to work on an extraction process that would allow the hormones to be taken orally. The first article in print from the Journal of Science in 1939 describes the use of subcutaneous hormone pellets in humans. Dr. Robert Greenblatt, professor and chairman at the Medical College of Georgia, had been using bio-identical hormone pellets since 1941. He reported the use of subcutaneous hormone replacement therapy pellets in humans in an article in the American Journal of Obstetrics and Gynecology in 1949.
Oral Bio-identical Hormone Replacement Therapy was first used for menopausal symptom relief in the 1930s, after Canadian researcher, Dr. James Collip, developed a method to extract an orally active estrogen from the urine of pregnant women. This estrogen product was marketed as the active agent in a product called Emmenin. After Dr. James Colip sold his extraction patent to a pharmaceutical manufacturer called Ayerst, Emmenin was subsequently replaced on the market when its manufacturer, Ayerst (later Wyeth Pharmaceuticals) found it much easier to deal with pregnant horses than pregnant women. Thus they began producing and marketing the more easily controlled and manufactured conjugated equine estrogens (CEE) in 1942 under the brand name Premarin which was short for Pregnant Mares Urine. Premarin contained at least 10 forms of estrogen with the most dominant ones being estrone (50-60%) and horse estrogen called equilin (22.5-32.5%) with less than 5% estradiol. Research and development of synthetic and equine hormones since the 1940s has provided the basis for most references on modern hormone replacement therapy (HRT). Current conventional practice which is derived from this research and heavily marketed to physicians and patients alike by the pharmaceutical companies is to prescribe non-bio-identical progestins and estrogens because these molecular compounds can be patented.
Oral conjugated equine (horse) estrogens (CEEs) were the first non-bio-identical hormones to be developed. Effective and clever mass marketing helped make estrogen-only replacement therapy (ERT) the most popular treatment for menopausal hot flashes until the mid-1970s, when a series of studies showed that continuous unopposed estrogen therapy alone was unequivocally associated with endometrial cancer. The endometrial cancer risk of unopposed continuous estrogen-alone therapy was estimated to be over 400 percent. The popularity of Estrogen Replacement Therapy then plummeted until scientists observed that endometrial cancer was seen less in women whose ovaries produced a proper balance of estrogen and natural progesterone. A synthetic non-human form of progesterone, “Provera”, called a progestin, was then developed to balance estrogens derived from the urine of pregnant mares in commercially available hormone replacement therapy preparations. To add to the confusion, the term “progesterone”, which is the natural hormone produced by the human body, was used interchangeably with the term “progestin” in medical, nursing and pharmaceutical literature. Prescribers often assumed them to be one in the same, although their molecular structure and effects on the human body were quite different.
From that point forward, women who still had a uterus received two prescriptions, an estrogen and a progestin. From 1975 to 1995, drug companies marketing these hormone preparations experienced phenomenal financial success and spent millions of dollars funding research to prove the benefits of their products for brain, heart, bone, bowel, breast and reproductive health. Some studies even attempted to prove these non- bio-identical hormones were cancer preventive.
In 1995 the FDA approved Wyeth to combine Premarin and Provera into a single pill, called Prempro and Premphase. This made it even easier for women to take and doctors to prescribe. Scattered reports of increased incidence of breast cancer in women taking these combinations of estrogen and synthetic progestins began surfacing. With their large financial reserves available, drug companies produced their own studies that revealed no increased risk and occasionally came up with a study that showed even a decreased risk of breast cancer. With so much confusion, most all physicians remained convinced they were doing the right thing for their patients.
In 1995, a landmark Nurses’ Health Study revealed a 41 percent increase in breast cancer risk in women who took these combination hormones for more than 10 years. However, the drug companies were able to negate much of the confidence in the study because it was uncontrolled and retrospective. Their advertising campaign worked and the prescribing habits of most physicians remained intact. The drug companies then came out with a series of studies that yielded promising benefits of Premarin/ Provera combination for heart disease, osteoporosis, colon cancer, vaginal atrophy, skin aging and even Alzheimer’s disease. By 1992, Premarin was the number one prescribed drug in the United States, with sales exceeding $1 billion in 1997. Even the American Heart Association agreed with the recommendation of taking postmenopausal hormone replacement therapy to protect the brain, bones, colon and heart. By 2002, approximately 22 million women were on hormone replacement therapy.
In January 2002, the HERS (Heart and Estrogen/Progestin Replacement) study was published. This was a well-respected prospective, placebo-controlled study of Prempro vs placebo in women started on the drug or a placebo following a heart attack. Women on Prempro had a 200 percent increased chance over the placebo of having a second heart attack within the first year of therapy. All of this leads up to the sentinel landmark study, the Women’s Health Initiative (WHI) Study was launched in 1993 and stopped prematurely in 2002 due to ethical concerns about increases in breast cancer, heart attacks, strokes, and blood clots. This large and often quoted study is further discussed in more detail in a separate article called Woman’s Health Initiative: The Origin of Confusion and Lingering Fear of Hormones.