~Female Hormone Modulation, Part 3

An Anti-Aging Hormone
In 1998, Dr. Helene Leonetti, M.D. (Bethlehem Obstetrics Clinic, Bethlehem, Pennsylvania), conducted a clinical study on the use of natural progesterone cream in the prevention of osteoporosis. The women being studied were in the immediate postmenopausal phase (1-5 years after menopause), which is when bone loss is most rapid. After the first year, the positive effects of progesterone became so apparent that the physicians overseeing the study were "unblinded." In other words, it became apparent to the physicians which women were receiving progesterone. The women in the progesterone group experienced the disappearance of lumps and bumps in their breasts, were less depressed, and had fewer hot flashes and better bone densities (although the time interval was too short for this to be significant).

An important point was that no women using progesterone cream experienced loss of bone density, while the placebo group showed slight bone loss. However, as the study continued to completion, although the women continued to have improved subjective symptoms as mentioned above, the bone densities did not change significantly (Leonetti, personal communication). Although these results have yet to be published, Dr. Leonetti theorized that the lack of statistical significance may have been partly because the women were all in early menopause when bone loss is at its highest. It is during this period of early menopause that estrogen deficiency causes the greatest amount of bone loss. Perhaps the bone-protecting results of progesterone would have been better if the subjects who were truly estrogen-deficient had been given appropriate doses of nutrients (such as magnesium, zinc, copper, and manganese), along with exercise and low-dose estrogen. One should not expect proges-terone by itself to protect against the age-related loss in bone density.

Anasti et al. (2001) also studied the effect of transdermal and vaginal natural progesterone on the uterine lining. Healthy post-menopausal women took conjugated estrogen alone for 14 days, followed by either transdermal or vaginal natural progesterone or placebo in combination with estrogen for another 4 weeks. Endometrial biopsies of all women showed a statistically significant decrease in uterine lining thickening (hyperplasia) compared to the placebo cream. This may be very important for women taking equine estrogen in terms of the protective effect of progesterone on the endometrium, once thought to be provided by synthetic progestogens (see comment, Leonetti et al. 1999).

John Lee (Lee et al. 1996), one of the world's foremost experts on progesterone therapy, has found studies showing that 20 times more progesterone is concentrated in brain cells than in blood serum levels. He postulates that progesterone may help prevent mental decline in the elderly, and that recovery after brain trauma is better if progesterone levels are higher.

Dr. Lee has also pointed out that progesterone has been shown to increase brain cell energy production while suppressing hyperexcitotoxicity. "Excitotoxicity" occurs when too much (or too little) of a neurotransmitter (such as glutamate) is released from brain cells. This type of toxicity is now considered a cause of brain aging and degenerative neurological disease. (Life Extension members take supplements such as methyl cobalamin and vinpocetine to help prevent nerve cell damage caused by excitotoxicity.) It now appears that progesterone also protects against this type of brain cell damage.

Progesterone May Help Prevent Breast Cancer

A large base of evidence suggests that progesterone is protective against, as well as a potential treatment for, breast cancer (Cowan et al. 1981; see also Ray Peat, M.D. at http://www.efn.org/~raypeat/sub.html and John Lee, M.D. at http://store.yahoo.com/johnleemd/trutabos.html). A study by Chang et al. (1995) showed transdermal estradiol increased breast cell proliferation rate by 230%, while transdermal progesterone decreased the cell proliferation rate by over 400%. A combination estradiol/progesterone cream maintained the normal proliferation rate. This is direct evidence that estradiol (a potent estrogen) stimulates hyperproliferation of breast tissue cells and progesterone prevents hyperproliferation.

A study by noted researcher Brent Formby contained insightful results. To determine why progesterone inhibits the proliferation of breast cancer cells, a variety of cancer cell lines with different receptors and different expression of genes were exposed to progesterone. Exposure to progesterone induced a maximal 90% inhibition of cell proliferation in T47-D breast cancer cells and no measurable response in MDA-231 progesterone-receptor negative breast cancer cells. Further research along the same lines should be able to specify exactly when progesterone therapy would be most effective (Formby et al. 1998).

Previous retrospective studies have shown that women undergoing breast cancer surgery during the luteal phase of the menstrual cycle (the span between ovulation and the start of menstruation), when progesterone is higher, have much longer survival times (Cooper et al. 1999; Badwe et al. 2000; Macleod et al. 2000). Angiogenesis (new blood supply) is essential for tumor growth, and vascular endothelial growth factor (VEGF) is one of the most potent angiogenic factors. Heer et al. (1998) suggested that since progesterone seems to lower VEGF expression, its lowering could possibly decrease the potential for tumor spread. Mohr et al. (1996) reported that women with a progesterone level of 4 ng/mL or more at the time of breast cancer surgery had a significantly better survival rate at 18 years than those with a lower serum level of progesterone. In those women with good progesterone levels at the time of surgery, it was revealed that approximately 65% were surviving 18 years later, whereas only 35% of the women with low progesterone levels were surviving (Mohr et al. 1996).

A study by Cowan et al. (1981) showed that the incidence of breast cancer was 5.4 times greater in women with low progesterone than in women who had favorable progesterone levels. Some final evidence confirming progesterone's protective effects on breast tissue comes from a study by Foidart et al. (1998b). A placebo gel, an estrogen gel, a progesterone gel, or a combination estrogen/progesterone gel was applied to women's breasts for 14 days prior to breast surgery. After surgery, the breast tissue was analyzed. It was found that estradiol increased breast cell proliferation and that progesterone greatly decreased proliferation (Foidart et al. 1998b).

As Dr. John Lee (Lee et al. 1996) explained: "The goal of progesterone supplementation is to restore normal physiologic levels of bioavailable progesterone." That is why testing saliva or blood or urine progesterone levels is important, especially for pre-menopausal women who are using progesterone cream to alleviate premenstrual syndrome symptoms. In women whose physicians are prescribing excess amounts of supplemental estrogen, the administration of progesterone may enable the dose of estrogen to be reduced, since progesterone restores sensitivity to estrogen receptors on cell membranes.

Note: Saliva testing or a 24-hour urine test for excretion of hormone metabolites is recommended by some medical experts once exogenous hormone replacement has been initiated. Published studies that compare serum blood measurements with urine and saliva have provided varying results. Therefore, the medical community is divided regarding which is a better test to perform when accessing hormone levels.

Potential Dangers of FDA-Approved Synthetic Progesterone Drugs

The issue of synthetic versus natural hormones is as important with progesterone as it is with estrogen. Just as the pharmaceutical industry created the dangerous estrogen drug Premarin, it has also produced a pseudo-progesterone named Provera. As with Premarin, the warning label on Provera contains many dangers, including the possibility of birth defects, breast cancer, blood clots, fluid retention, acne, rashes, weight gain, and depression. Drugs such as Provera are classified as "progestins," not as progesterones. The side effects of Premarin and Provera may be the main reason that women stop taking their replacement hormones. Side effects are definitely the reason that hormone replacement therapy (HRT) has such a questionable reputation.

An alternative to artificial progestins is the option of using natural progesterone products. Products that can be purchased over the counter (such as ProFem) use progesterone derived from soybeans. Not only are such soy-based natural progesterones far safer than synthetic drugs, they are as easily utilized as the real progesterone manufactured within the human body. The preferable forms of natural progesterone are creams that are rubbed into appropriate areas of the body. This route of administration bypasses the liver and allows hormone delivery to the place where it is needed the most. For example, progesterone cream applied to the breast slows cell proliferation and eases breast pain. As to safety, according to Dr. Christiane Northrup: "There is virtually no danger of overdose."

In addition to the established and dangerous progestins such as Provera, the FDA has approved a drug called Prometrium, which is an oral pill containing 100 mg of natural micronized progesterone to be taken daily. This can result in the liver going into overdrive in an effort to excrete this overabundant supply of progesterone. Some experts believe that progesterone cream is better utilized and much more economical. Dr. Foidart, in another study on transdermal replacement hormone therapy, states that avoidance of the "first passage effect" (through the liver) is ensured by the transdermal application of hormones and probably explains the superiority of this route of hormone administration (Foidart et al. 1998a). Transdermal progesterone cream has now been well researched and shows an antiproliferative effect on the uterine lining (Anasti et al. 2001). It is also excellent for the resolution of vasomotor symptoms such as hot flashes, as shown in a double-blind study (Leonetti et al. 1999).

Natural progesterone should not be confused with the synthetic FDA-approved progestins that cause many side effects. Synthetic progestins do not provide the broad spectrum of benefits that have been shown for natural progesterone.

Hormone Deficiencies: DHEA

DHEA (dehydroepiandrosterone) is a natural steroidal hormone secreted by the adrenal gland, gonads, and brain. DHEA is produced by both men and women. DHEA is the hormonal precursor of estrogen and testosterone; therefore, taking DHEA might raise the levels of these hormones. DHEA is a good starting place for hormone modulation in the aging female.

While there have been contradictions in the research on DHEA, it appears to be a rejuvenative hormone to at least a moderate degree, improving mood, neurological functions, immune system functioning, bone growth, energy, and feelings of well-being. In a review of research, Morales et al. (1995) reported that DHEA, given until the patients' blood levels matched those found in their teenage years, resulted in "remarkable improvement of physical and psychological well-being in both genders. This finding in addition to the absence of side effects provides great promise for the replacement strategy."

It should be noted that because DHEA may raise estrogen levels, the Life Extension Foundation recommends that it be taken with indole-3-carbinol (plus melatonin at night) to provide a safeguard against breast cell proliferation. (Melatonin is a pineal hormone with multiple benefits and no significant side effects. Most importantly, it appears to protect against breast cancer.) It is best to take DHEA early in the day, while melatonin should be taken only at bedtime.

Some menopausal and postmenopausal women experience a decline in testosterone production, which can cause persistent vasomotor symptoms such as hot flashes. A study found that an increase in testosterone and DHEA-S levels seemed to protect against vasomotor symptoms of menopause. This study also found that the body mass index (BMI), a measurement of obesity, was higher in those with low DHEA-S levels (Overlie et al. 2002).

Because DHEA naturally converts to both estrogen and testosterone, supplementation with DHEA can be used to raise both estrogen and testosterone levels. However, a potential problem of this route is that there is no control over what the body will naturally do with the DHEA (i.e., how much turns into estrogen and how much turns into testosterone). Regular blood tests to assess estrogen and free testosterone blood status can provide guidance as to whether supplemental DHEA is providing the body with the hormones it needs. If DHEA does not properly cascade down into optimal levels of estrogen and testosterone, it is more desirable for women to be given the direct hormones that they need.

DHEA also has additional benefits. For example, long-term supplementation with DHEA has been demonstrated to improve insulin sensitivity and lipid profiles (Casson et al. 1995). A patient's symptom score should be carefully monitored, as should all hormone levels.

Although women usually have less DHEA than men, both sexes lose DHEA at about the same rate, suggesting that it is an age-related decline, not just a result of menopause. Peak levels are typically reached when women are in their third decade of life, following which they begin to lose approximately 2% per year (Wright et al. 1997).

Caution: Women with estrogen-dependent cancer should not take DHEA. Individuals with existing liver disease (such as viral hepatitis or cirrhosis) should consider taking DHEA sublingually (under the tongue) or using a topical DHEA cream to reduce the amount of DHEA entering the liver. DHEA is converted by the liver into DHEA-S (dehydroepiandrosterone sulfate). Those with liver disease should have liver enzyme levels carefully monitored to be certain that DHEA therapy does not cause liver disease to worsen. Women who are currently using hormone replacement therapy may still have inadequate levels of DHEA. DHEA blood testing can help determine the ultimate amount of DHEA supplement. Women are advised to consult their physician regarding maintaining appropriate hormone levels.

Lack of Libido Is Not Just in Your Head

The problem of loss of sexual desire is far more common in women of all ages than is recognized. Causes of decreased libido range from a variety of medical ailments to psychosocial influences which are beyond the scope of this protocol. However, hormones can play a significant and often undiscovered role.

Research with menopausal women has been the origin of much of our knowledge in this area. Davis (1998) points out that using androgens with postmenopausal women successfully increases their sexual desire. However, the bigger picture is that androgen (testosterone) levels fall significantly throughout the reproductive years and probably affect desire from an early age (Longcope 1998; Gelfand 1999). It has been shown that circulating levels of androgens play an important role in psychologic and sexual changes that occur in menopause, whether naturally or surgically induced.

Although estrogen replacement often seems to accommodate these changes, some women may require combination treatment. Results from clinical studies showed that in some women a combination of estrogen and testosterone replacement provided greater improvement in psychological (e.g., fatigue, lack of concentration, and depression) and sexual function (e.g., inability to have an orgasm and decreased libido) than estrogen alone (Bachmann 1999, 2001; Gelfand 1999; Sarrel 1999). In addition, research by Braunstein (1999), reported as a Reuters Health News Release, indicated that testosterone delivered through a transdermal patch increased women's perceptions of orgasmic pleasure.

Some androgens, along with DHEA, decline steadily from early adulthood (Longcope 1998). Other androgens show more decline closer to menopause. Treatment with androgens is safe and effective for these dysfunctions when given at low levels and when paired with progesterone (Slayden 1998). Many women lose sexual desire after giving birth. Many of these sexual problems are directly related to general postpartum depression. The goal is to modulate the estrogen/progesterone/testosterone balance to reach earlier, healthier levels, reducing as many negative postpartum outcomes as possible, including loss of libido.

Hormone Modulation
  • Blood Testing
  • Saliva Testing
  • Urine
  • Making Right Choices
  • Safe Hormone Modulation
  • Natural Estrogen
  • Natural Progesterone Cream
  • DHEA Replacement
The process of achieving proper female hormonal balance is not a one-step procedure. Ideally, women should make the lifestyle changes recommended in this protocol to empower themselves in their personal healthcare. It is possible to take shortcuts in regulating hormones, and many positive outcomes may be achieved even without careful modulation. However, for optimal benefit, precise testing and fine-tuning of various hormone-modulating agents is recommended, because balance is the key to success--with the overriding goal of keeping risk to a minimum. For this reason, it is recommended that women have periodic blood, urine, and/or saliva testing to monitor the hormone balance as well as the symptoms, although some practitioners use symptoms alone to guide treatment.

Both natural and synthetic hormones come with synthetic instructions--the dosages specified on the labels are for the "average" woman--one who does not exist. While these dosages might achieve much of the symptom relief advertised by the products, it would be unusual to realize optimal hormone modulation for all the hormones discussed using only the amounts listed. While this protocol will suggest dosages to be taken, these doses should be considered as starting points, not as final goals. The individualization that offers the greatest amount of long-term health improvement is based on testing and feedback.

We do not regulate the temperature in our homes by simply setting the air conditioning thermostat on a "recommended" number and leaving it there indefinitely. We check the actual temperature, assess our comfort level, and make adjustments for time of day and season of the year. If we are this careful with air conditioning, why would we be reluctant to adjust such a critical matter as hormone level?

Adjustment can be achieved only by self-evaluation and testing before and after hormone-affecting supplements are taken. Despite labels recommending "one capsule a day," only personal symptom changes and saliva, urine, or blood levels can determine what actually works well. Testing before any supplements are taken provides results called "baseline" measurements that may be invaluable in the future. If new medical problems arise, knowing the earlier baseline measurements can allow for more accurate diagnosis and treatment. Testing may be performed in several ways.

Blood Testing

This measurement technique has the advantage of widespread established technology and standards. Most published studies that document the safety and efficacy of proper hormone replacement therapy rely on blood tests, rather than saliva testing.

As mentioned earlier in this protocol, there is difference of opinion among experts regarding whether blood levels provide an accurate reflection of the amount of hormone in the tissues, in comparison to saliva and urine. Clinicians in practice also offer difference of opinion regarding their experiences with serum testing of hormones. While one group of physicians advocates serum testing as the most accurate, another equally knowledgeable group of physicians argues that saliva or urine testing is much more accurate.

It is critical to remember that different laboratories have different standards. For example, Laboratory A has methods of testing that leads it to declare that a given hormone for a 30-year-old, nonpregnant woman has a "normal range" of 4 to 7. Laboratory B may use different specimen collection methods or measurement techniques and declares the "normal range" of scores to be between 3.2 and 6.4. Standards from one laboratory should not be used to evaluate testing by another source. In addition, it is impossible to give a representative sample of all the possible optimal or even average scores because these figures change based on age, pregnancy status, menopausal status, the particular day within each woman's menstrual cycle, and time of day. For example, cortisol norms can have substantial differences based on whether the sample was taken in the morning or in the afternoon. Therefore, each woman must compare her current scores with the average scores for a desired age from the norms of the same laboratory.

Regarding estrogen testing, at initial evaluation, 80-90 pg/mL is the desired serum range of estradiol for women by most laboratory standards. Serum estriol levels are usually almost immeasurable in a nonpregnant woman unless she takes estriol by prescription. For estrone, a specific desired starting level is not given in this protocol because our recommendation is to avoid supplementation with this type of estrogen unless it is noticeably low after therapy is initiated.

Saliva Testing

This measurement technique does not have the same standards as blood testing, but it is available by mail order and offers a degree of convenience. Standards are important when attempting to emulate the results of published studies. Some argue that saliva testing is more accurate than blood testing; others disagree. Since saliva testing has not been available as long as blood testing and does not offer the standardized parameters that blood testing offers, hormone replacement is recommended by using a symptom scale as well as by using parameters.

Saliva testing is an accurate way to examine the tissue levels of hormones during therapy; however, there is one major defect. If the patient has any amount of gingivitis or has blood in the mouth from dental flossing at the time of testing, the accuracy of the test becomes poor. In such a situation, the saliva hormonal levels would read very high.

Urine

The use of the 24-hour urine test may be the most accurate form of measurement because hormones are secreted in "bursts" rather than steadily throughout the day (Wright et al. 1997). By collecting a full day's volume of urine, a woman gets a more complete picture of her actual levels. The test measures all of the metabolites and by-products of the hormones over a 24-hour period, and the average female's hormones fluctuate throughout the day. The shortcoming of this test is the difficulty involved in collection: every drop of urine must be gathered during the 24-hour period. Additionally, some experts argue that the urine test is a reflection of metabolic waste products (metabolites) from the hormones rather than the hormones that exist in the tissues themselves. Proponents of this testing method claim that a look at these metabolites can, by extrapolation, provide a more accurate understanding of what is going on in the tissues in a 24-hour period than either serum or saliva testing.

When evaluating the effectiveness of either a new supplement or a change in dosage of an ongoing supplement, it is recommended that testing intervals of 60-90 days are used. Because some hormones gradually convert into other hormones (known as a "cascade"), waiting at least 60 days ensures accuracy. There is a urine test that requires only one sample instead of having to inconveniently collect urine in a bag over a 24-hour period. (This test will be described under the estrogen drug section of this protocol.)

Making Choices That Are Right for You

While a positive physician/patient interaction is always beneficial, such cooperation is even more important for women who are dealing with hormonal issues. Some women insist on having a female healthcare provider, fearing that their PMS or menopausal complaints might be dismissed too easily or treated too routinely by a male physician. These fears are sometimes warranted, but the key to choosing and keeping a physician is to find someone (male or female) who listens and who includes you in the healthcare feedback loop. Symptom improvement may be accomplished with minimal effort, but achieving true hormone modulation often requires time and patience.

The selection of hormone modulation goals is a complex decision based on personal philosophy, resources, time, and fortitude. Philosophically, a woman must strike a personal balance between acceptable methods and acceptable outcomes. Choices involve types of hormones used, their sources, the costs, side effects, desired results, and both short- and long-term benefits and risks. In addition, there is a choice to be made in terms of outcome priorities: is symptom reduction sufficient by itself or are optimal blood levels also required? These are the types of decisions to be made by each woman.


Continued . . .


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