A question I commonly hear when a woman consults me about a health challenge she is facing is, “Do you think it’s my hormones?” Hormones are chemicals produced by the body that regulate actions of cells and organs. While men and women alike depend upon daily hormonal activity for their well being and survival, women are much more attuned to the importance of these substances.

Most men can go through life without giving any thought to how thyroid hormones are regulating their metabolism, how adrenal hormones are allowing them to handle the stresses of life, or how testosterone is maintaining their muscle strength and sense of well-being. Women, however, are reminded monthly of the importance of hormonal balance in maintaining the natural rhythm of their bodies.

When glands fail to manufacture adequate amounts of hormones, substances must be administered to maintain the actions that are regulated and maintained by those hormones. The substances used may be chemicals that imitate the actions of the hormones produced by the body or they can be the hormones themselves. When the substances that are administered are exactly the same as those produced by the body they are said to be bio-identical. Not all hormone replacement products are bio-identical. Chemicals that are not the same as those manufactured by the body, but which mimic the actions of body hormones, can also be used to augment their activity when the body fails to produce the amount of hormone required to maintain proper balance.

In the August 2006 issue of Health by Design I wrote about the benefits of providing bio-identical progesterone to the body when menstrual irregularities appear and after menopause occurs. I contrasted the actions of bio-identical progesterone in the body to those of non-identical substitute called medroxyprogesterone acetate:

“Medroxyprogesterone acetate (MPA) is quite effective in imitating the effects of progesterone upon the uterine lining. The similarities stop there, however. The two substances behave much differently elsewhere in the body.

MPA tends to cause weight gain; progesterone stimulates fat burning and weight loss. MPA is associated with depression and sleep disturbances; progesterone eases depression and improves sleep quality. MPA increases the risk of abnormal blood clots, no such risk has been found with progesterone. MPA increases the frequency of headaches, particularly migraine headaches; progesterone decreases the frequency of migraine headaches. MPA can trigger release of breast milk; progesterone blocks the production of breast milk. MPA can cause fatigue and sleepiness; progesterone tends to improve energy levels.

It is therefore not surprising that while MPA has been shown to increase the risk of breast cancer, studies such as that of Dr. Gino Tutera, which followed 976 women supplementing progesterone over a ten year period, have shown no such effect. To the contrary, evidence is accumulating that suggests progesterone has a protective effect and actually reduces the risk of breast cancer over time.”

I did not discuss the other major female sex hormone, estrogen, at that time, but differences between bio-identical estrogens and non-identical estrogens are significant. Every woman should be aware of her choices when she finds herself in need of hormonal support.

The human body produces three estrogen compounds: estriol, estradiol, and estrone. Estradiol is the dominant form of estrogen in the human body; it is also the most potent of the three forms. While the ovaries are the primary site of estrogen production in the body, estrogens are also produced in the adrenal glands, fatty cells, the brain, and arterial linings. It is the decline in estradiol production during and after menopause that is most responsible for the occurrence of hot flashes and the development of vaginal dryness.

Estriol is produced in significant amounts during pregnancy, when it is manufactured by the placenta. The hormone is credited with bringing about the improvement in multiple sclerosis that is often seen during pregnancy, and it is believed to be responsible for the decreased incidence of breast cancer in women who have been pregnant compared to those who have not.. Estriol levels tend to remain stable through menopause.

Estrone is the least prevalent form of human estrogen. Estrone can be converted to estradiol as needed. It is believed that providing a pool of material that can readily be converted to estradiol is the primary role of estrone in the body.

The leading form of estrogen replacement product in the United States is called conjugated estrogens. Only one conjugated estrogens product is available. It is called Premarin. Patented in 1942, the name is derived from the source of the estrogens it contains – Pregnant mare urine. When the patent was originally granted the only estrogens that were known to be present in the product were estrone and equilin. Over time, many additional estrogenic substances in Premarin have been identified. It is now known that at least thirty forms of estrogen are present. Most of these are variations of equilin and equilinin – so named because they are unique to equines (horses).

While dosages of Premarin continue to be based upon their estrone content, it is now known that the estrogenic effects of Premarin are at least 2.5 times greater than would be produced by the estrone it contains. This is cause for concern, since estrogen excess has been shown to increase the risk of breast and uterine cancer, blood clotting disorders, and stroke.

Premarin was approved for sale as a prescription drug in 1947. Sales gradually rose throughout the 1950s, 1960s, and 1970s. Sales declined sharply in the late 1970s after studies demonstrated that women who took estrogen replacement therapy after menopause were at greater risk of developing uterine cancer. Once it was demonstrated that the risk could be controlled by adding the hormone progesterone or a drug with progesterone-like effects to the regimen sales began to grow once again.

Premarin became the number one prescription drug in the United States in 1993 and held that position for nearly a decade. In 2001 world-wide sales reached $2 billion. This made Premarin the premier drug of its manufacturer, Wyeth Pharmaceuticals. PremPro, a product that combined Premarin and Provera, Wyeth’s brand of medroxyprogesterone acetate, was also enjoying record sales. Unfortunately for Wyeth, a devastating report was released that same year.

A study called the Women’s Health Initiative, which was designed to compare the outcome of women receiving Premarin, PremPro, or a placebo, had begun in 1993. Plans were to continue the trial through 2005. The PremPro portion of the study was abruptly halted in May 2002, however, when an interim analysis of the data revealed that women taking the drug were approximately 50 % more likely to be diagnosed with breast cancer.

While the study did not show an increase in the number of breast cancers reported with the use of Premarin alone, it did find that women taking Premarin had 50 % more abnormal mammogram reports and underwent 33 % more breast biopsies than women who were not on the drug. Women on the drug also tended to have larger tumors that were more likely to spread to lymph nodes than women who were taking the placebo.

Sales plummeted. Premarin and PremPro sales fell 68 % between 2002 and 2004 and Wyeth’s profits declined from $4,447,000,000 in 2004 to $1,234,000,000 in 2002. While some women simply stopped taking hormone replacement therapy for menopause, many turned to bio-identical hormones for relief of their symptoms.

Bio-identical estrogens are not new. Their use actually predates that of Premarin. A preparation of estriol, called Emminin, was introduced in the United States in 1933. It was a year later, in 1934 that researchers at the University of Toronto published a paper detailing a process for extracting estrogen from the urine of pregnant mares.

Emminin was extracted from urine obtained during human pregnancies, but the process was too slow to meet the demand. Ayerst Pharmaceuticals, which would later become Wyeth, recognized the potential of using horses as the estrogen source, patented the process in 1942, and obtained permission to begin marketing the product in 1947.

Drugs launched prior to 1995 were normally given 17 year patent protection before a competitor would be allowed to offer a generic form of the product. It is therefore remarkable that over 65 years after the drug was patented Premarin remains free of generic competition. The reason given by the FDA for refusing to allow anyone to introduce a generic brand of conjugated estrogens is that the exact number and type of estrogens in Premarin remains unknown.

The composition of the drug remains unknown? It is hard to imagine how a drug with an unknown composition can be approved for use. It is even more difficult to understand why such a drug has been granted a monopoly for over half a century. How has the drug remained on the market as serious risks including formation of blood clots, loss of blood flow to a portion of the lung, stroke, and breast abnormalities have emerged?

In March 1999 the FDA did approve a synthetic conjugated estrogens product, Cenestin, for short-term use in relieving menopausal symptoms. Shortly after its release I received a call from a Cenestin salesman. He said that he knew that I was interested in natural products and was excited to be able to inform me that a plant-based estrogen replacement product was now available.

“What’s in it?” I asked.

“We’ve successfully synthesized nine of the estrogens found in Premarin,” he declared proudly.

“Why did you do that?” I inquired.

“Because Premarin is the gold standard,” he replied.

“It would have been nice if you had chosen to follow the human standard,” I responded. The phone went silent. I have not heard from him since.

While it is true that Cenestin is synthesized from plant constituents, it is much more horse friendly than human friendly. Six of the nine estrogenic substances it contains are unique to horses and are not found in the human body.

The FDA had refused to approve Cenestin as a generic form of Premarin in 1997, stating that the active ingredients in Premarin had not been adequately defined and therefore no manufacturer could prove that its product was identical to Premarin. The makers of Cenestin were required to reapply as a new drug. Approval for marketing was given only after studies demonstrated that it was effective in treating menopausal symptoms. The FDA withheld approval for long-term use of Cenestin in the prevention of osteoporosis, reserving that indication for Premarin alone, again citing the reason that the active ingredients of Premarin have not yet been adequately defined.

In contrast, the composition of bio-identical estrogen preparations is known with total accuracy. The most commonly prescribed bio-identical product is called Triest. It is a combination of estriol, estradiol, and estrone. Estriol is used as the dominant estrogen because studies, one over a period of 35 years, have shown that that estriol provides protection against breast cancer. Other studies have demonstrated the estriol supplementation reduces the risk of Alzheimer’s disease and improves the status of multiple sclerosis. Estriol has also been shown to improve bone density and lessen the risk of atherosclerosis (hardening of the arteries).

Unlike conjugated estrogens, estriol supplementation does not increase the risk of uterine cancer. In fact, no adverse consequences have ever been reported from the use of bio-identical estrogens!

Given the known risks of conjugated estrogens and the proven benefits of bio-identical estrogens, the choice of which approach to take when dealing with menopausal symptoms should be straightforward. Unfortunately, this is not the case.

Wyeth did not take the precipitous drop in its profits lying down. In October 2005, the company filed a "citizens' petition" demanding that the FDA ban bio-identical hormones that compete with Premarin and PremPro.

Over 70,000 women, pharmacists, and doctors wrote to the FDA, the overwhelming majority asking the Agency to reject Wyeth's attempt to shut down the competition and preserve access to bio-identical hormones. Incredibly, the FDA sided against the citizens and with Wyeth, claiming that estriol is a “new and unapproved drug” whose “safety and effectiveness is unknown.” The January 9^th decision banned the sale of estriol in the United States.

The FDA admitted that no adverse events related to the use of estriol had ever been reported. It is hard to imagine how a substance manufactured by the human body in large quantities during pregnancy to ensure the health of the mother and baby could be called a “new and unapproved drug of unknown safety.” In addition, a monograph on estriol is contained within the United States Pharmacopeia (USP) which has been the official public standards-setting authority for all prescription and over-the-counter medicines, dietary supplements, and other healthcare products manufactured and sold in the United States for over 185 years.

When illogic rules the day it is often helpful to “follow the money trail.” That certainly seems appropriate in the case of the FDA ban on the use of estriol.

As strange as it may seem, the FDA’s budget is tied to sales of the very drugs it is supposed to regulate. The more drugs sold the more money the FDA receives. Plummeting sales of Premarin and PremPro not only cut profits at Wyeth; they also triggered deep cuts in the FDA’s budget. Since bio-identical hormones are prepared and sold by compounding pharmacists, who do not fall under the jurisdiction of the FDA, the FDA receives no money from the sale of bio-identical hormone prescriptions.

Estriol remains available in the United States through a loophole. Pharmacists can currently prepare and sell bio-identical estrogen prescriptions if they file an “investigational new drug” application with the FDA. This is problematic, however, since many women rely upon prescription drug insurance coverage to cover the cost of their medications. Since insurance companies routinely deny payment for investigational drugs, most women now must decide whether to pay out-of-pocket to obtain the benefits of bio-identical estrogen or to accept the risks of the conjugated estrogens covered by their insurer. The situation is unprecedented. No agent detailed in the USP had ever been treated as a new drug prior to the FDA’s January 2008 ruling against estriol.

While it is currently being sold as a “new and investigational drug”, it is highly unlikely that estriol will ever receive new drug approval from the FDA. When Cenestin’s application for approval as a generic conjugated estrogens product was denied, its patent holder reapplied for FDA approval as a new drug. The company was required to spend large sums of money on studies demonstrating the drug’s effectiveness in relieving menopausal symptoms. Unlike Premarin and Cenestin, estriol is a normal body constituent that cannot be patented. Thus there is no incentive for anyone to fund the type of studies the FDA demands for approval of new drugs.

Other pharmaceutical companies have been quick to note Wyeth’s success. In April, 2008 pharmaceutical giant GlaxoSmithKline filed a “citizen’s petition” asking the FDA to ban the sale of nutritional supplements that are seen as competitors of GlaxoSmithKline’s diet drug Alli. It is feared that if the FDA rules in GSK’s favor the ruling could impact the availability of many other nutritional products.