By Jonathan V. Wright, M.D. with contributions by Christa Hinchcliffe, N.D. and Wendy Ellis, N.D.

If you're a woman, your average life expectancy is about 80 years old. That means you're going to spend more than one-third of your life in a postmenopausal state, facing all the adverse health effects associated with reduced levels of the hormones your body made internally before menopause (estrogens, progesterone, DHEA, testosterone, thyroid hormones, melatonin, and others). These effects range from mild but annoying-things like increased fatigue and decreased libido-to serious threats to your ability to lead a normal daily life - osteoporosis, muscle weakness, atherosclerosis, loss of cognitive function, and many more.

And those of you men reading this aren't out of the woods either. Although your hormones decline more gradually, men face very similar challenges.

But there is a way to effectively prevent many of these problems, "diseases of aging" as they've come to be known, and promote longevity in both women and men during the later stages of your lives. The only problem is, many of us are afraid to use it.

Concerns about the risks associated with "hormone replacement therapy" have been a hot topic of discussion, especially over the last few years, since the results of the "Women's Health Initiative" were released.

Those of you who receive the Health eTips e-letter might recall reading last month about a recent survey conducted by researchers at Stanford University, which found that fewer than 30 percent of women remember this pivotal study. What does seem to have made a lasting impression are the dangers that were uncovered by that trial, namely increased risks of heart attack, stroke, and cancer.

But the HRT in the "Women's Health Initiative" study used horse estrogens and a "space alien" progestin (not natural progesterone), neither of which have any business being in your body. So it's critical to make the distinction between HRT using hormones that are completely foreign to human bodies and the kind used in bio-identical HRT (BHRT), which exactly mimic what your body produces (or produced) naturally all on its own before menopause and andropause set in. Unfortunately, the mainstream media - even articles by "leading science writers" - very rarely make that distinction. And, as a result, I get lots of questions about BHRT safety every day, from Nutrition & Healing readers and Tahoma Clinic patients.

Today I'll do my best to answer them all in one comprehensive article. So let's start with the question that is typically forefront on everyone's mind: How do you know for sure that BHRT is safe?

Know where your safety stands

Even though I wrote the first prescriptions for bio-identical HRT in the early 1980s, and in that time (as far as has been reported to me) only one individual out of several thousand has developed a cancer that could possibly be related to hormones, I'm the first to admit that my experiences are not "controlled research."

Fortunately, many aspects of BHRT safety have been researched in depth. And numerous studies have found that it has many advantages over conventional "horse and alien molecule" HRT, but two of the most striking are that, unlike the "other" form, BHRT decreases cardiovascular risk, as well as estrogen-related cancer risk.¹-¹⁰

But BHRT research still has some gaps. There's not been time for long-term controlled studies. Also, very few studies are done on a cellular level because the hormones used in BHRT-estradiol, estriol, sometimes estrone, progesterone, testosterone, DHEA, and others-are not always used by your cells in exactly these molecular forms. Instead, they get "metabolized" by your body into other molecules (which we'll get into in just a bit). Research so far has found some of these metabolized hormones to be pro-carcinogenic, others anti-carcinogenic, and the status of others is still uncertain. "Ratios" between some of these hormones are also important.

But even though at present these metabolites can't be monitored at the cellular level, they can be at a "whole body" level, which is how we maximize BHRT safety.

The most comprehensive and accurate way to monitor hormone metabolites is with a 24-hour urine test. Many of the people I work with are surprised that I don't recommend blood testing to measure hormone levels. But there are a few factors that explain why blood testing isn't the best choice.

When your body produces hormones internally, they're secreted in "pulses," (bursts and pauses) and when you use BHRT, you supplement with the hormones once or twice a day. So they're not continuously circulating throughout your body at steady levels, which makes obtaining an accurate measurement from a blood sample extremely difficult: Blood levels of any hormone can be quite variable depending on the time of day the sample is drawn. Urine testing, on the other hand, determines the entire amount produced-or supplemented-in a 24-hour period.

Except with testosterone, blood tests also don't distinguish between the "free" and "bound" forms of hormones. And, according to researchers, the "bound" forms are inactive. So nearly all of the estrogens and progesterone measured in blood are the inactive "bound" form. The "free" forms-the active forms -are actually not measured at all. But urine testing measures the sum of free and "conjugated" hormonal steroids. (Conjugated steroids are ones that have combined with other simple molecules.) The "free" form of any hormone is the most active form, but the "conjugated" form can be active, too, so it's beneficial to know how much of these types of hormones are in your body, as opposed to a measurement that includes forms that research has found to be inactive.

One other quirk of blood testing is that estriol-one of the most important protective estrogens-is practically unmeasurable in blood samples by most labs, while in urine estriol is found in greater quantities than nearly any other single estrogen. While they aren't absolutely certain why, experts think this may occur because even though considerable estriol is secreted every day, it's "cleared" from the blood very rapidly.

And on top of these drawbacks, blood testing just isn't presently available for many of the steroid metabolites that are important for ensuring BHRT safety. In addition to estriol, at present blood tests for 2-methoxyestradiol (a "good" estrogen), 4-hydroxyestrone (considered the "worst" estrogen), androstanediol (a "good" testosterone), and others are not available.

What about saliva testing? Well, it's true that saliva testing is convenient and non-invasive, and somewhat accurate for younger individuals not using BHRT. But its main drawback for practitioners is that salivary levels of steroid hormones for individuals using BHRT are "sky-high," and usually bear no resemblance to normal physiologic ranges. Also, even though saliva testing is said to measure the "free" form of steroid hormones, studies have shown that steroid binding proteins do appear in saliva, so it's possible that these measurements include some "bound"(or inactive) hormone, too.¹¹-¹² And, like blood testing, saliva testing is not available for many of the metabolites necessary to monitor for safety.

So urine testing is really the "gold standard" for monitoring BHRT safety. This test keeps tabs on literally dozens of steroid hormones and their metabolites. It does this by testing each urine specimen with something called gas chromatography (GC). According to nearly all experts, GC is unsurpassed in its potential for determining a multitude of steroid metabolites simultaneously in a single specimen. The GC is also coupled with "mass spectrometry" (MS), which literally identifies the "molecular fingerprint" of each individual steroid molecule.

Not all estrogens are created equal: Which ones should you REALLY be concerned about?

Now that we've covered the testing you'll need to undergo to keep BHRT safe, let's move on to the actual hormones involved, starting with estrogen, and talk about which ones are can be cause for concern and why.

There are more than 20 circulating estrogens in the body. Estrone, estradiol, and estriol are frequently thought of as the main players, although researchers have found that 2-hydroxyestrone is also present in large quantities. ¹³ Estrone and estradiol are potent estrogens, generally thought to be procarcinogenic -when they're acting alone, that is. But when you add the right amount of estriol to the mix (as Mother Nature intended), it neutralizes those effects by acting as an anti-carcinogen. Before menopause, most women's bodies secrete more estriol than estrone and estradiol, so BHRT generally contains more estriol, too.

Next there are the hydroxyestrogens. Like estriol, 2-hydroxyestrone (and other 2-hydroxyestrogens) are considered to be "weak" but anti-carcinogenic estrogens. 16-alpha- hydroxyestrone (and other 16-alpha- hydroxyestrogens), on the other hand, are pro-carcinogenic. This is where the "2/16 ratio" comes into play, and allows BHRT users to get the benefits of these estrogen metabolites without putting themselves at risk.

Considerable research shows that the ratio of 2-hydroxyestrogens to 16-alpha-hydroxyestrogens can predict breast cancer risk for pre-menopausal women. Higher 2/16 ratios indicate lower breast cancer risk, and low 2/16 ratios (particularly those less than 1.0) indicate higher risk. While this ratio doesn't appear to be helpful for predicting breast cancer risk in post-menopausal women who aren't using BHRT, it's been my experience (although no actual research data exists), that it is indeed predictive for post-menopausal women who are using BHRT.

And before you men tune out, those 2-hydroxyestrogen and 16-alpha-hydroxyestrogen measurements are important for you to Research has found men in the highest third of 16-alpha-hydroxyestrogen had the highest risk of prostate cancer, while men with in the highest third of 2-hydroxyestrogen had the lowest risk.¹⁶

If your 24-hour urine test shows that your 2/16 ratio is low, there are two simple ways to boost it back into the "safe" zone. Start by adding more cruciferous vegetables (broccoli, cauliflower, bok choy, cabbage, Brussels sprouts), flaxseed, and soy (but not too much soy for men) to your diet. These foods can all help raise your 2-hydroxyestrogen levels, which, in turn, will help move your 2/16 ratios in a favorable direction.

You can also take supplements of the active compound in the cruciferous vegetables, a substance called di-indolylmethane (or DIM). Usually 100 milligrams two to three times daily can bring a low 2/16 ratio back up to a safe range. (One thing to keep in mind: Many practitioners still recommend supplements of the precursor molecule to DIM, called indole-3-carbinol, or I3C. But I3C only becomes active after it's transformed into DIM by stomach acid. And since so many individuals are low in stomach acid, I've found that it's more effective just to use DIM itself.)

While 16-hydroxyestrogens are pro-carcinogenic, the estrogen metabolites that appear to pose the biggest threat to your health are the ones with the number "4" in front of them-4-hydroxyestrone and other 4-hydroxyestrogens. These are the ones considered to be the most carcinogenic of all estrogens, stimulating the growth of both breast and prostate cancer.¹⁷ And, at present, only the 24-hour urine test using GC-MS can measure your levels of these metabolites (so you see, again, why urine testing is such an important part of BHRT safety).

If your levels of any 4-hydroxyestrogens are higher than normal, you should also increase your intake of cruciferous vegetables and/or start taking DIM. One research report found that I3C supplements could lower 4-hydroxyestrogens, so cruciferous vegetables and DIM can very likely do the same thing.¹⁸

Unlike patent medicine versions of HRT, the human body is all about balance when it comes to hormones. Since we naturally produce some pro-carcinogenic estrogens, Mother Nature also made sure we produce anti-carcinogenic ones as well. One of these anti-carcinogenic estrogen metabolites is 2-methoxyestradiol. It's actually only found in very small quantities in the body. But this is one of those situations where a little goes a long way. Small quantities or not, 2-methoxyestradiol is a very potent anti-carcinogen. So potent, in fact, that one patent medicine company has recently "renamed" it Panzem and is trying to get the FDA to "approve" it as a patent "drug." (Unfortunately, the clinical trials on Panzem are using enormous and entirely un-natural quantities of 2-methoxyestradiol introduced into the body in an entirely un-natural way: by swallowing it. Estrogens and other steroid hormones simply don't-and shouldn't-enter the body through our GI tracts!)

One group of researchers has also found that even very tiny quantities of 2-methoxyestradiol (less than one micromole, for the technically inclined) are effective against uterine fibroid (leiomyoma) cells.¹⁹ Others are finding that 2-methoxyestradiol may be a very important factor in protecting against the artery damage that leads to atherosclerosis.

Since 2-methoxyestradiol plays such important roles in the body, it's crucial to keep your own levels in a normal range so that this powerful metabolite can offer the maximum amount of protection possible. 2-methoxyestradiol is something known as a "methylated" estrogen, so nutrients that induce the process of "methylation" may help increase its levels. Folate and vitamin B12 both help stimulate methylation, so if your 24-hour urine test shows low 2-methoxyestradiol, work with a practitioner skilled and knowledgeable in nutritional and natural medicine to determine the best doses of these and other nutrients to help increase your levels.

Taking on testosterone-safely and naturally

When you're talking about estrogen, you can bet that testosterone isn't far behind. The good news is, things are a little simpler when it comes to monitoring this hormone for safety (which, I suppose proves that men who claim that women are "complicated" are at least partially correct!). Although there are testosterone metabolites that you do need to keep track of, there aren't as many as there are with estrogen.

The first testosterone metabolite on the list is one you've probably already heard of, since there are patent medicines designed to lower it: DHT (di-hydrotestosterone). But as you read in the September issue of Nutrition & Healing, using one of those patent medications or too much alpha-linolenic acid (ALA), zinc, or saw palmetto can lower DHT levels too far. This does lower overall prostate cancer risk, but, as strange as it sounds, it actually increases the risk of developing a more aggressive form of the disease. Although research isn't definitive on this point, it appears that this could occur because low levels of DHT can lessen the formation of an anti-cancerous testosterone metabolite called androstanediol, which is actually made from DHT. In fact, it's likely that the ratio between DHT and androstanediol is even more important than the level of either one on its own.

Another aspect of BHRT safety that men need to keep tabs on is "excess aromatization," a technical term used to describe the entirely natural but quite unhealthful process-for men-of metabolizing testosterone into too much estrogen. Aromatization itself is normal: Even the most masculine men need some estrogen for their bodies to operate at peak performance. But when overactivity of that process transforms testosterone into too much estrogen, problems-like prostate enlargement and even prostate cancer—can occur.

Excess aromatization becomes more common with increasing age, but it's even more common in men with insulin resistance. Type 2 dia-betics always have insulin resistance, but if you haven't been diagnosed with diabetes, that doesn't necessarily mean you don’t need to worry about excess aromatization: Insulin resistance usually occurs years—even decades—before type 2 diabetes is ever diagnosed.

If you have type 2 diabetes or an increased risk of insulin resistance (which you do if type 2 diabetes runs in your family), check with a physician skilled and knowledgeable in bio-identical hormone use to see if your 24-hour urine test shows excess aromatization.

Fortunately, there are two very effective ways to slow aromatization to a normal rate. One is a combination formula of Chinese botanicals called "Myo-min" (from Chi Enterprises). I've observed that two or three tablets twice daily will almost always return excess estrogen to normal. The other male "excess estrogen normalizer" is the flavonoid chrysin, derived from passion flower. One important caveat, though: It's typically not very effective in capsule or tablet form. The best delivery system of chrysin is the liposomal spray form, (from LipoLab) which I have found to be effective for most men. Two sprays twice daily usually does the job. Both Myomin and liposomal spray chrysin are available through natural food stores, compounding pharmacies, and the Tahoma Clinic Dispensary.

Researchers have also found that melatonin can inhibit aromatization. Sometimes it can take rather large doses-up to 20 milligrams a day-to do the job, though. While this amount is free of serious side effects, it can make you more drowsy or groggy than you would typically be in the morning, so it may not be useful for everyone.

When BHRT "doesn't work"

Over the years, I've encountered a small percentage of women who try BHRT for menopausal symptoms and get no results at all, even after several months of treatment. Their hot flashes, mood swings, insomnia and other symptoms continue despite BHRT use, even at quantities considerably higher than usually necessary for other women.

Once again, the 24-hour urine test usually comes to the rescue and finds the explanation. More often than not what testing uncovers are very high levels of all estrogens, a situation technically referred to as "estrogen hyperexcretion" or "failure of estrogen retention." This happens when the liver is metabolizing the estrogen much too rapidly, and is literally "kicking most of it out" via the bowels and the urine.

After doing some library research, in the late 1990s I found that the 300-600 micrograms of the compound cobalt chloride almost always corrects this situation, although it does happen very gradually.²⁰ According to one group of researchers, cobalt reduces the total number of estrogen- metabolizing enzymes, called cytochromes,²¹ so that (in this case) less estrogen is "kicked out" (or "hyperexcreted"), and more is retained in the body. With more estrogen retained by the body, symptoms of low estrogen decrease and ultimately disappear.

Ordinarily, it takes three to six months for the cobalt chloride to "reset" estrogen metabolism in the liver. But once the patient's menopause symptoms have been alleviated and the 24-hour urine test shows normal levels of estrogen excretion, the cobalt can be discontinued.

I've also observed instances of "testosterone hyperexcretion" (or "failure of testosterone retention") in men, and one case of cortisol hyperexcretion. All were found with the 24-hour urine test, and all corrected with the same approach.

If you've tried BHRT and it just hasn't worked for you, check with a physician skilled and knowledgeable in BHRT treatment and monitoring for a 24-hour urine test to see if this is your problem. If it is, you'll also need the doctor's help and supervision to use low dose cobalt chloride treatment.

Putting BHRT safety into practice

As technical as all the preceding information has been, it truly does make an impact on your daily functioning. The following examples might do a better job of showing you how the 24-hour urine test can help make sense of hormone levels and the symptoms that imbalances can cause.

Frank was 72 when he came in to the office complaining of muscle weakness, lack of stamina, and erectile dysfunction. Among various other supplements, he was taking 100 milligrams of pregnenolone daily. Pregnenolone is sometimes called the "mother of all steroids," as it is at the top of the hormone metabolism tree, and may be converted to any other steroid metabolite at all: cortisol, estrogen, testosterone, DHEA, aldosterone-any of them.

24-hour urine testing using GC/MS determined his testosterone levels to be on the very low end of normal. His estrone was three times higher than his testosterone, actually at the same level as most premenopausal women!

Frank stopped taking the pregnenolone and started taking testosterone instead. Three months later, Frank returned with improved stamina, muscle strength, and erectile function. His follow-up urine test confirmed a decrease in estrone to normal male levels, as well as an increase in testosterone values.

Barbara was in her late 30s, the last of nine sisters. All eight older sisters had had breast cancer, and Barbara wanted to do everything she could to avoid getting it herself. She was actually working at the Tahoma Clinic at the time and had heard about the 2/16 ratio test from employees at nearby Meridian Valley Labs.

Although these estrogen metabolites had been researched for years, Meridian Valley Labs was the first lab to introduce the test for practitioners-and Barbara was the first woman to get the test done.

Her test showed 2-hydroxyestrogens to be very low, and her 16-hydroxyestrogens high—her "2/16" ratio was just 0.5, which definitely indicated that she was at higher risk for breast cancer. Barbara's first step was the same one I recommended to you earlier: She added more broccoli, cauliflower, cabbage, ground flaxseed, and soy to her diet. But her next test disclosed a 2/16 ratio of 0.6-not a significant improvement. So she added di-indolylmethane (DIM) supplements (60 milligrams three times a day) to her extra cruciferous vegetable intake. Several weeks later her 2/16 test was up a bit-but only to 0.8. Barbara continued eating as many cruciferous vegetables as she could and increased her DIM dose to 120 milligrams three times a day, and finally boosted her 2/16 ratio up over 1.0.

Michael was 51 when he came to the Tahoma Clinic. In his mid-40s he'd started having symptoms of prostate enlargement (BPH)-getting up more than once at night to urinate, decreased force of his urine stream, and a bit more difficulty getting urination started. He read about and started taking a standardized preparation of saw palmetto, 160 milligrams three times daily. Over three to four months, his symptoms faded to when he reported as "almost un-noticeable," and stayed that way for several years.

But when he came in for his appointment, I was concerned about the amount of saw palmetto he was taking, and also that he wasn't using any supplemental zinc or essential fatty acids such as ALA or GLA (gamma-linolenic acid, which is actually more effective for BPH than ALA). So I recommended he take a 24-hour urine test.

Michael's test showed that his 5-alpha-reductase was severely over-inhibited. I explained (as you read earlier) that while reducing levels of this enzyme along with DHT may lower his over-all risk of prostate cancer, it could actually increase his risk of developing a more aggressive form of prostate cancer. I also explained that zinc and essential fatty acids such as GLA and ALA are essential nutrients, and saw palmetto isn't, so these essential nutrients should be the first line of defense for reducing over-active 5-alpha-reductase. He eliminated the saw palmetto, and over several months was able to find quantities of zinc and GLA that worked for him, both for symptom control and for normalizing his enzyme activity as seen on the 24-hour urine test.

These are just a handful of examples of people who have benefited from bio-identical hormone replacement therapy along with careful monitoring of not only the hormones themselves, but also their equally important metabolites. Of course, BHRT continues to evolve. While there's no longer any doubt that BHRT is safer than horse hormones and patented "space alien" progestins, BHRT is not and can never be perfectly safe. After all, our own internally produced hormones aren't perfectly safe either: Research shows that even younger people whose own bodies produce higher levels of sex hormones have a somewhat higher hormone-related cancer risk.

But unlike those versions of HRT the patent medicine companies continue to try to force on you, keeping BHRT as safe as possible is often as simple as taking a regular urine test and working with your doctor to adjust any imbalances naturally. JVW

References:
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² "Differential effects of oral and transdermal postmenopausal estrogen replacement therapies on C-reactive protein," Thromb Haemost 2003; 90(1): 124-131
³ "Effect of Oral and Transdermal Estrogen Replacement Therapy on Hemostatic Variables Associated With Venous Thrombosis: A Randomized, Placebo-Controlled Study in Postmenopausal Women," Arterioscler Thromb Vasc Biol 2003; 23(6): 1,116-1,121
⁴ "Differential Effects of Oral and Transdermal Estrogen/Progesterone Regimens on Sensitivity to Activated Protein C Among Postmenopausal Women: A Randomized Trial," Arterioscler Thromb Vasc Biol 2003; 23(9):1671-1676
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¹¹ "Identification and measurement of sex hormone binding globulin (SHBG) and corticosteroid binding globulin (CBG) in human saliva," Acta Endocrinol (Copenh) 1986; 112: 603-608
¹² "Detection of corticosteroid binding globulin in parotid fluids: evidence for the presence of both protein-bound and non-protein-bound (free) steroids in uncontaminated saliva." Acta Endocrinol (Copenh) 1988; 119: 56-60
¹³ "Menstrual cycle effects on urinary estrogen metabolites," J Clin Endocrinol Metab 1999; 84(11): 3,914-3,918
¹⁴ Siiteri P, et al. "Prospective study of estrogens during pregnancy and breast cancer risk." Era of Hope Abstracts 2002, Department of Defense-Congressionally Directed Medical Research Programs (cdmrp.army.mil/bcrp/era/abstracts2002/P13_Chemoprevention/P13_combined.pdf), accessed 10/12/07
¹⁵ "Altered Hydroxylation of Estrogen in Patients with Postmenopausal Osteopenia," J Clin Endocrinol Metab 1997; 82(4): 1,001-1,006
¹⁶ "Urinary Estrogen Metabolites and Prostate Cancer: A Case-Control Study in the United States," Cancer Causes & Control 2002; 13(10): 947-955
¹⁷ "Potential biomarker for early risk assessment of prostate cancer," Prostate 2006; 66(14): 1,565-1,571
¹⁸ "Quantitative determination of 3,3'-diindolylmethane in urine of individuals receiving indole-3-carbinol," Nutr Cancer 2001;41(1-2): 57-63
¹⁹ "Estrogen metabolite 2-methoxyestradiol induces apoptosis and inhibits cell proliferation and collagen production in rat and human leiomyoma cells: a potential medicinal treatment for uterine fibroids," J Soc Gynecol Investig 2006; 13(8): 542-550
²⁰ "Bio-identical steroid hormone replacement: selected observations from 23 years of clinical and laboratory practice," Ann NY Acad Sci 2005; 1,057: 506-524
²¹ Maines MD, Kappas A. "Metals as regulators of heme metabolism," Science 1977; 198: 1,215-1,221

This article was published in the December, 2007 issue of the Dr. Jonathan V. Wright's Clinical Nutrition & Healing newsletter, and is presented here with permission.