Friend or Foe?
Estrogen therapy has been used in the US for more than 70 years to alleviate the unwelcome symptoms of menopause, including hot flashes, vaginitis, and mood swings. Unfortunately, the widely publicized halting of studies on some well-known estrogen products generated a lot of fear and confusion about all hormone therapies, especially estrogen. Follow-up studies have compounded the issues with contradictory results regarding both the benefits and the risks of estrogen therapy, leaving women wondering: “Are estrogens friend or foe?”
The History of Estrogen Therapy
Until the last century, most women did not live long after they achieved menopause. As life expectancy has increased, so has the attention given to the symptoms and changes that affect women once they pass this milestone.
Estrogen’s benefits for treating menopausal symptoms were discovered in the 1930s, and it gained widespread use in the 1940s following the introduction of the first commercial estrogen preparations. Typically, these preparations were (and still are) oral medications derived from purified female sex hormones from pregnant mare urine (branded as Premarin) or synthetically derived from plant materials.
In The Menopause Industry, Sandra Coney notes that from the late 1940s into the early 1970s the medical community completely accepted as fact that menopausal women must naturally face tremendous psychological loss during this “change of life.” Their menopausal symptoms were often attributed to emotional stress at the loss of the ability to bear children; as a result, many menopausal women were frequently prescribed antidepressants instead of, or in addition to, estrogen therapies.
By the late 1960s, modern medicine was returning to the view that menopausal problems were primarily caused by estrogen loss. A New York gynecologist, Robert A. Wilson, was instrumental in setting this perception. In his best-selling book Feminine Forever, Dr. Wilson advocated prescribing estrogen to prevent menopause altogether and promoted the use of estrogen therapy via his Wilson Foundation, funded by pharmaceutical companies.
Premarin was originally approved by the US Food and Drug Administration (FDA) in 1941 for treating moderate to severe hot flashes and severe dryness, itching, and burning in and around the vagina. However, over time, Premarin and other estrogens began being used “off label” to prevent and treat a wide range of conditions affecting older women, from wrinkles and depression to heart attacks and osteoporosis. In fact, it wasn’t until 1986 that the FDA approved Premarin and other short-term-acting estrogens as a treatment for osteoporosis.
That same year, 1986, the Postmenopausal Estrogen/Progestin Interventions (PEPI) trial began, which assessed levels of HDL in more than 800 women ages 45-64, receiving different hormonal regimens. This trial was one of the few that compared a bioidentical hormone to their conventional options. This study showed that Premarin and bioidentical progesterone (Prometrium) produced more favorable increases in HDL levels than Premarin combined with a non-bioidentical progestin. Thus, the PEPI study demonstrated a clear difference between the effects of bioidentical progesterone and non-bioidentical medroxyprogesterone.
Claims that estrogen might prevent or improve cardiovascular disease continued to gain ground in the 1980s and 1990s. Healthcare practitioners had long observed that women’s relative protection against heart disease and stroke typically wanes at menopause. Many theorized that estrogen levels help protect the cardiovascular system, possibly by lowering cholesterol levels. To learn more, the National Institutes of Health (NIH) funded the Women’s Health Initiative (WHI) to determine if taking Premarin and/or Prempro shielded healthy older women against heart disease, stroke, osteoporosis, and breast cancer.
In 1997, the NIH began two WHI clinical trials involving 16,000 women aged 50-79, designed to study the effectiveness of Premarin and Prempro, which is a combination of Premarin and medroxyprogestrone, a synthetic progestin (no bioidentical hormones were used in the WHI studies). Both studies were halted early because of adverse effects. NIH stopped the first study in 2002 when women taking Prempro for more than four years were found to have an increased risk of breast cancer, heart disease, stroke, and blood clots. They stopped the second trial in 2004 when they found an increased risk of stroke among women over 60 who had received hysterectomies and were taking Premarin; however, this second study also showed no increase in breast cancer risk or heart attacks.
The results of the WHI studies have been widely publicized and debated. Many researchers noted significant flaws in these studies. In a May 2008 paper “In Defense of Estrogen,” Phyllis J. Bronson, a PhD chemist, notes that the selection of participants was seriously flawed, as many women already had hypertension or diabetes. She continues: “Further complicating matters, the majority of the women had started on hormone replacement therapy well long after the onset of menopause, an average of 10-15 years later.” Also, none of the women had their hormone levels evaluated prior to the study.
With the media hype that followed the halting of the WHI studies, many women abandoned all types of estrogen therapy, and began asking “Are estrogens friend or foe?” To answer that question, it is important to understand this hormone’s many functions, the different types of estrogen produced in a woman’s body, and the range of treatment options available. With this knowledge, a woman and her healthcare practitioner can more accurately determine if a particular estrogen therapy, at a particular time in her life, is an appropriate course of treatment.
Three Key Estrogens
Most people don’t realize that the human body produces—and needs— not just one, but many kinds of estrogens. We will limit our discussion to the three primary estrogens:
- Estrone (E1)
- Estradiol (E2), specifically 17-beta estradiol
- Estriol (E3)
Estriol: The “Weak” Estrogen with Strong Protection
Many healthcare practitioners believe estriol (E3) is too weak in a non-pregnant woman to warrant their attention. Therefore, most women only have their estriol levels tested during pregnancy, when this estrogen dominates.
Edward J. Conley, MD, feels this view is dangerously wrong, stating that estriol “is naturally high in women for a reason: To protect your breasts from overstimulation and overproduction of breast cells.” In his book Safe Estrogen, he writes that estriol is the safest estrogen because, unlike estradiol and estrone, it is not converted to the metabolites that have been linked to breast cancer. In addition, Dr. Conley says estriol “appears to have a strong attraction for your estrogen receptors,” meaning that estriol blocks the dangerous metabolites from overstimulating breast tissue.
European women have used estriol for decades, Dr. Conley notes, and report that it excels at treating vaginal or urinary problems, particularly when given intravaginally. Postmenopausal women with recurring urinary tract infections have been shown to improve while using an intravaginal estriol cream. Estriol appears to help prevent UTIs and vaginitis by restoring mucus and correcting the pH balance.
A small but intriguing study of multiple sclerosis patients points to the possibility that estriol may help patients with inflammatory diseases. Many women with autoimmune diseases improve during pregnancy when estriol levels are high. In the study, patients with the relapsing-remitting form of multiple sclerosis were shown to significantly improve while taking oral estriol therapy.
“Estriol is the weakest estrogen that reduces post-menopausal symptoms,” says Dr. Conley. “It is associated with significantly lower risks of breast and uterine cancer than the stronger estrogens.” The only downside to estriol appears to be that it does not protect against bone loss as well as the other two estrogens.
The strongest and most active form of estrogen is estradiol (E2). It is made by the ovaries, adrenals and fat cells, and comprises 5-10% of the total estrogen circulating in the blood. Nearly every cell in the body houses receptors for estradiol. Estradiol is generally acknowledged as the most important estrogen molecule for relieving the key menopause complaints, as well as increasing bone mass and improving cholesterol levels.
Estrone (E1) also makes up about 5-10% of a premenopausal woman’s total circulating estrogen, but it is about 12 times weaker than estradiol. In younger women, estrone is mainly converted from estradiol in the liver. After menopause, women produce estrone mainly in fat cells, where it is derived from testosterone. For this reason, older women who are overweight often have high circulating levels of estrone.
Although it makes up as much as 80- 90% of the circulating estrogen, estriol (E3), receives little clinical attention outside of pregnancy because it is extremely weak—about 80 times weaker than estradiol (see sidebar). During pregnancy, estriol is produced in large quantities. In nonpregnant women, it is produced in the liver as a byproduct of the conversion of estrone, which is itself converted from estradiol (in younger women).
Testosterone can also be transformed into estrogens. While some other tissues can also trigger estrogen production, the total amount of estrogens is greatly diminished after menopause. In addition, shifts in the ratio of the three key estrogens may cause less estriol to be present in the blood.
When properly balanced in the body, estrogens may improve health in almost every respect. “A wealth of data suggests that if E2 … is started at the proper age it has profound, beneficial effects on all aspects of a woman’s healthy biology, including moods and emotion, heart disease, memory, bone density and cancer risk,” Dr. Bronson says.
“Estrogen makes everything grow,” is how Ericka Schwartz, MD, explains it. In The Hormone Solution, Dr. Schwartz notes that it makes the lining of the uterus grow to prepare for pregnancy, matures the ovum, promotes the growth of the egg and the fetus, and keeps vaginal tissue moist and well developed. Following menopause, estrogen remains important for cell growth and renewal; when it is lacking, renewal suffers in skin, hair, bones, and nerve cells.
Receptors for the key estrogen hormones are located in both the epidermis and the dermis and in the skin’s blood vessels. Estrogens circulating in the blood are believed to raise fluid retention and enhance elasticity in the skin, and may also boost collagen production.
According to researcher Mark Brincat, PhD, “skin collagen content and skin thickness are increased in women on estrogen replacement therapy.” Dr. Brincat also notes that topical estrogens may reduce hot flashes through a direct effect on the skin. He believes that estrogen may have a positive neurotransmitter effect on the skin itself, allowing it to properly communicate with the brain to control body temperature.
Dr. Brincat and others have observed that estrogens’ effects on skin thickness often parallel their effects on a woman’s bone mass. Women may desire to keep healthy and beautiful skin, but they really need to maintain bone health if they want to live a long and active life.
Throughout our lives, bones continuously grow and break down. Testosterone and progesterone stimulate bone formation, while estrogens act to inhibit bone deterioration by improving calcium absorption. “Research shows that as much as 75 percent of the bone loss seen in the 20 years following menopause can be blamed on hormone loss,” writes Gillian Ford in Listening to Your Hormones. “While diet and exercise help, neither can stop bone loss if estrogen levels are below normal,” she adds.
For many women, another concern after menopause is sexuality. “Some women naturally produce estrogen in their adrenal glands in sufficient quantities to enjoy sex after menopause,” notes Ford, while others, who do not produce enough estrogens, may experience vaginal dryness.
In women, the highest number of estrogen receptors is found in the vagina. Estrogens serve to maintain the shape and flexibility of the vagina, and also ensure the thickness and lubrication of its lining, Ford explains. “When estrogen supplies diminish, the vaginal tissues become dry, narrow and less pliable. The vagina may shorten, and the entrance to the vagina may become so narrow that intercourse is painful or impossible.” In addition, estrogens increase sexual response and the quality of a woman’s orgasm.
While no one argues the role that estrogens play in a woman’s sexuality, many are surprised to learn that they also play an important role in maintaining a healthy brain. Researchers have long realized that sex hormones have profound effects on neurotransmission— the ability of nerves to communicate properly. “Mood, memory and other cognitive ability depend upon proper neurotransmission,” writes Edward L. Klaiber, MD. In Hormones and the Mind, Dr. Klaiber relates how he personally participated in research that proved treatment with estrogens could help severely depressed women who had been resistant to antidepressant medications.
Estrogens actually improve neurotransmission in several ways: by increasing the production of mood-regulating neurotransmitters; by increasing the number of neurotransmitter receptors in nerve cells; and by also helping to maintain the structure of dendrites, the branching structures of the brain, which allow neurons to “talk.” In addition, estrogens work together with growth factors to promote the growth of nerve cells in the brain.
In postmenopausal women, estrogens have been shown to increase brain activity, particularly short-term verbal memory and abstract reasoning. A number of studies have demonstrated that women given estrogens receive increased blood flow to the cerebral cortex, a requirement for high cognitive functioning. Alzheimer’s disease is associated with reduced cerebral blood flow, indicating that estrogens may possibly help prevent this disease, although studies have not yet proven a direct effect.
Heart health is one key area where estrogens’ effects are still very murky. While some major studies have found no association between estrogen therapy and cardiovascular disease, others show increased heart and blood vessel risks for those receiving different estrogen therapies. Clearly, estrogens have complex effects on cardiovascular function (see our Matters of the Heart newsletter for a more detailed synopsis) and are likely to affect women differently, depending upon a number of factors, especially medical history. For example, in most women, estrogens act to dilate blood vessels, which results in lower blood pressure, considered a boon to the heart. Yet Ford notes that in approximately 1 in 20 women, orally administered estrogens can actually raise blood pressure. This is one area where estrogens straddle the fence, potentially being both friend and foe, depending on individual circumstances.
Known Estrogen Risks
Several studies have linked estrogens to increased risk of some forms of cancer. This does not mean that they cause cancer, but simply that women using estrogen therapy tend to have a higher than expected rate of cancer development that cannot be explained by other factors.
Breast cancer is probably the most feared condition linked with estrogen therapy. However, like all cancers, it arises from multiple conditions that interact in complex ways. Risk factors now believed to predispose a woman to breast cancer include lifestyle choices (obesity and pregnancy, for example), environmental exposures (such as chemicals or medications), and family history.
As women age, the risk for all cancers, including breast cancer, increases. Scientists have recently discovered that cancer is not simply caused by malignant cells that rage out of control, but also seems to require the failure of the body’s own mechanism for killing off damaged cells.
In grossly simplified terms, high levels of estradiol in the blood can lead to increased cell growth, whereas high levels of progesterone often cause more cell death to occur. Many studies have shown that unopposed estrogens (i.e., estrogens without progesterone) can lead to uncontrolled breast cell growth, which in some cases may trigger cancer.
As touched upon earlier, unopposed estrogens have also been linked to the thickening of the uterine lining, a risk factor for endometrial cancer. Moderating the risk of developing either breast or uterine cancer is possible by balancing the use of estrogens with the appropriate amount of progesterone. Progesterone balances the power of estrogens by reducing the number of cell receptors for estrogens and increasing the level of an enzyme that converts estradiol to estrone sulfate, which is easily expelled.
Some practitioners note that estriol may be the best estrogen to give to women with above-average risk for these cancers.
As with any treatment, estrogen therapy can cause side effects in some patients. Unopposed estrogens increase the risk of:
- Weight gain
- Impaired blood sugar control
- Anxiety and irritability
- Gallbladder disease
- Blood clots
- Resumption of the menstrual cycle or spotting
- Swollen breasts
Once the body adjusts to estrogens with progesterone, these symptoms often disappear. Unfortunately, some women continue to have problems. The reason may be associated with the delivery form and/or their body’s ability to make use of the hormones, or another underlying condition; this is why it is so important to bring up any concerns you may have with your healthcare practitioner, so your treatment can be adjusted to meet your needs.
How estrogens are delivered— orally, sublingually, topically, or intravaginally—affects the body’s ability to use them. This stems from the fact that orally administered drugs are absorbed through the digestive tract and partially metabolized by the liver before they reach the bloodstream and the rest of the body. This is called the “first pass” effect. Avoiding this effect provides greater absorption of the hormones into the bloodstream.
However, the liver and the digestive system also ensure that the body does not wind up with too much of the circulating hormones. When either the liver or the bowel are not working properly, estrogens that need to be excreted are sometimes recycled and reabsorbed into the bloodstream, which can lead to an accumulation of excess estrogen.
Insufficient progesterone and testosterone (among other hormones) also help determine whether estrogens act as friends or foes. “Estrogen and progesterone are designed to balance each other, to keep each other in check,” reminds Dr. Schwartz in The Hormone Solution. “We cannot live in a healthy state without their balanced presence in our bodies.”
Accumulation of Estrogens
Progesterone does not seem to help all women keep their estrogen levels in check. There are two key reasons this can occur. The primary reason is that nearly all of us actually receive more estrogens than we realize from our diet and from environmental sources. In particular, we are exposed regularly to estrogen-mimicking compounds that can occupy estrogen receptor sites in cells throughout our body, affecting hormone signaling. Secondly, a woman’s liver and/or digestive system may not adequately eliminate excess estrogen.
Estrogens (or substances that mimic their effects) may build up in our bodies slowly, as we gain exposure to naturally weak estrogens in plants, stronger synthetic estrogens from birth control pills or hormone therapies, and long-lasting estrogen mimics from pesticides and other environmental sources.
According to biologist Ray Peat, PhD, the amount of estrogens in our diets is significant enough to have toxic effects in at least some cases. “People under stress, or who have a thyroid deficiency, or who don’t eat enough protein, typically have elevated estrogen levels,” says Dr. Peat.
Interestingly, plant-based estrogens (phytoestrogens) have been suggested as a means of cancer prevention. These weak estrogens, found in foods such as soybeans, are believed to block estrogen receptor sites that would otherwise be occupied by stronger, more toxic estrogens. “This may be one reason that lifelong vegetarians have a lower risk for estrogen-dependent health disorders such as breast cancer,” says Lindsey Berkson in her book Hormone Deception. In addition, unlike synthetic or environmental estrogens, phytoestrogens spend little time in our bodies because they are not stored in fat or tissue. Their effects may be beneficial—but not if they simply “pile on” more estrogens than the body can handle.
“Natural estrogens are present in our body all the time,” explained Dr. Wade Welshons, as quoted in Berkson’s “All About Estrogen” chapter. “If substances from outside enter the body add to, subtract from, or alter natural hormone signaling, some functions in the body are bound to change.” This may explain why some women who take the equine-based estrogens find that these “foreign” estrogens are difficult to process.
Any physical ailment that prevents the body from properly metabolizing estrogens can also contribute to an accumulation. As mentioned earlier, digestive problems play a role in estrogen buildup. People diagnosed with, or at high risk for, liver disease or gallstones are also more likely to suffer from estrogen excess.
At menopause, levels of the estrogen hormones plummet 70 to 75% resulting in life-altering symptoms for many women and forcing them into a dilemma: Should I be taking hormone therapy? And, if I do, will estrogens be my friend or foe? When considering hormone therapy, women need to discuss their specific list of symptoms with their healthcare practitioner, and ask a lot of questions, starting with:
- Are estrogens really what I need? Why?
- What are my risks, based on my medical history?
If, after conferring with her practitioner, a woman chooses to try estrogen therapy, there are still more decisions to make and questions to ask:
- Which estrogens are best for my needs?
- How much and for how long?
- What are my treatment options?
- Which of those options is bioidentical?
With feedback among the patient, practitioner, and pharmacist, the prescribed treatment can—and should—be adjusted as needed to alleviate the symptoms. Other hormones may also be necessary to completely resolve symptoms and restore the quality of life.
Finally, women should keep informed about their healthcare choices, especially with regard to hormone therapies, and stay on top of who is determining what those choices are. Health standards are very political and always have been. Powerful pharmaceutical companies are well represented on the government committees and health organizations that recommend which products should be made available to the public—or not. Profit motives can influence the availability of treatment options, thereby interfering with the patient/ practitioner relationship. Who is better equipped to make those choices than an informed patient and her practitioner?
Connections is a publication of Women’s International Pharmacy, which is dedicated to the education and management of PMS, menopause, infertility, postpartum depression, and other hormone-related conditions and therapies.
This publication is distributed with the understanding that it does not constitute medical advice for individual problems. Although this material is intended to be accurate, proper medical advice should be sought from a competent healthcare professional.
Publisher: Constance Kindschi Hegerfeld, Executive VP – Women’s International Pharmacy
Co-Editors: Julie Johnson; Carol Petersen, RPh, CNP – Women’s International Pharmacy
Writer: Kathleen McCormick – McCormick Communications
Illustrator: Amelia Janes – Midwest Educational Graphics
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