Forty-five million women are menopausal in the United States today; another 3.5 million women will become menopausal each year. Based on life expectancy trends, women face the prospect of spending the last one-third to one-half of their lives in a state of hormonal imbalance. The quality and quantity of your life after the menopause occurs may be largely determined by how well you manage your hormonal and biochemical state.

FEMALE HORMONE REPLACEMENT

The ovaries are not only the only glands to produce progesterone and estrogens. The adrenals make some as well. Normally, when the ovaries stop producing enough female hormones, the adrenal supplies the difference. However, many women do not have the adrenal reserve to pick up the extra demand and smooth the transition to lower hormone levels needed for mature women who no longer are capable of carrying a pregnancy. Chronic social and emotional stress, poor nutrition, and impaired glucose metabolism are among the most common reasons women's adrenal reserves become exhausted.

Here are a few common reasons for considering female hormone replacement therapy.

  1. MENOPAUSAL SYMPTOMS such as hot flashes, emotional swings, flushing, sweats, etc. While female hormones are effective for this, my patients report excellent success using a supplement designed to detoxify the liver.
  2. VAGINAL ATROPHY causes dryness, irritation, discomfort during sexual relations, etc. Hormone creams and oral preparations are appropriate options. An alternative might be to support the ovaries or adrenal glands in hopes they will produce sufficient amount of hormones.
  3. OSTEOPOROSIS PREVENTION is a concern for nearly every woman living in industrialized society. Osteoporosis is dependent on many other factors beside female hormones. In fact, osteoporosis is not a problem in other areas of the world despite their minimal use of female hormones. See my osteoporosis handout for more information.
  4. REDUCE YOUR RISK OF HEART DISEASE. It has been shown in women after menopause. It is well known that men have a higher incidence of heart disease than women. It is thought that female hormones may provide some protection against heart disease that is lost when a woman goes through menopause. Certainly there are many other factors involved than simply female hormone levels. Fat and sugar metabolism, diet, stress, family/genetics, exercise, weight, thyroid metabolism, smoking, high blood pressure, etc. have very significant effects on the development of heart disease. The contribution of female hormones may be less important if these other conditions are not addressed/corrected.
  5. TO MAINTAIN PRE-MENOPAUSAL HORMONE LEVELS could be considered a way of maintaining youth, etc. However, it is difficult to argue why all mammals' ovaries mature and stop producing hormones and eggs. The wisdom of our design and evolution must be accounted for.

**It is important not to confuse replacement doses with the high dosages used for birth control.**

PROGESTERONE: This hormone is produced by the adrenal gland and the ovary. It can be converted into other hormones including estrogen. The term progesterone should only be used to describe the actual natural hormone. Synthetic products such as Provera® do not have the same properties as progesterone. It can not be converted into other hormones and may not have the same effect on thyroid hormone metabolism, bone metabolism, balancing estrogen's effects, etc. Natural progesterone is poorly absorbed because it tends to be destroyed by stomach acid. For this reason there are different forms available including micronized progesterone taken under the tongue (sub-lingually), progesterone in oil (so it passes through the stomach undigested), or as a cream applied to the skin. Convenience, cost, and effect will determine which may be best for you.

ESTROGEN: Is a term usually used to describe three different hormones with different properties - estriol, estrone, and estradiol. Each of these hormones in turn has several metabolites. Some promote cancer development, others seem protective. For example, estriol is reported to have anti-carcinogenic potential. A blend of these hormones in a natural form and normal amount is available by prescription as Tri-estrogen. It is a more natural alternative to Premarin® made from horse's urine or conjugated estrogen.

TESTOSTERONE: Although commonly thought to be primarily a "male hormone," testosterone is found in women as well and is every bit as important to your health and well being as the other hormones. Testosterone can be converted into estrogens and is often used to improve mood, muscle development, osteoporosis and sex-drive. It is important not confuse natural testosterone with the synthetic forms such as methyltestosterone, which can cause liver damage.

CYCLING: The body's response to female hormones (and many other hormones as well) is blunted if the same dose is administered every day. Just as with the normal menstrual cycle, female hormone levels change at various times throughout the month. It seems logical that hormone replacement should also be cyclical with a period of rest. For some adjusting the dosage to match the pre-menopausal cycle is optimal.

OPTIONS TO HORMONE REPLACEMENT: For women who have at least some ovarian function, nutritional supplements designed to stimulate and/or nourish the ovaries can be tried. They seem to work best in women who are nearing menopause or who have just entered menopause. Adrenal support can be tried as well. A variety of herbs and herbal combinations are another option.

Starting around age 45-50 years the amount of estrogen naturally produced by the ovaries declines, which causes a wide range of "menopausal" symptoms including hot flashes, night sweats, depression, vaginal dryness, anxiety, metabolic shifts, forgetfulness, and premature aging.

Estrogen replacement therapy (ERT) remains controversial. On the one hand, hormone replacement seems to play a role in the prevention of osteoporosis and heart disease, and the reversal of some aspects of neurological decline. The anti-aging benefits of estrogen replacement therapy include:

  • Enhanced skin smoothness, firmness, and elasticity
  • Enhanced moistness of skin and mucus membranes
  • Enhanced muscle tone
  • Reduced genital atrophy and enhanced sex drive in women
  • Reduced menopausal miseries such as hot flashes and anxiety
  • Reduced risk of heart disease and osteoporosis
  • Reduced risk of colon cancer
  • Improved memory and neurological function
  • Protection against Alzheimer's disease
  • Enhanced immune function
  • A greater feeling of well-being

One of the major benefits of estrogen therapy is prevention of the bone loss associated with menopause. Postmenopausal women taking estrogen experience 50% fewer bone fractures than women of comparable age who have not taken estrogen.

However, estrogens have been documented to cause cancer. One report showed that women taking estrogen and a synthetic form of progesterone, (classified as progestins*) had a 32 to 46% increase in their risk of breast cancer (New England Journal of Medicine, June 15, 1995). This study showed that the carcinogenic risk of estrogen-progestin replacement therapy became most pronounced when it was used for 10 or more years. Another report (American Journal of Epidemiology May 1995) showed that long-term estrogen replacement therapy increased the risk of fatal ovarian cancer. This 7-year study included 240,073 pre- and post-menopausal women. After adjusting for other risk factors, women who used estrogen for 6 to 8 years had a 40% higher risk of deadly ovarian tumors, while women who used estrogen drugs for 11 or more years had a startling 70% higher risk of dying from cancer of the ovaries. Cancers of the breast, uterus, and ovary account for 41% of cancer incidence in U.S. women.

As you are no doubt aware, breast cancer is epidemic, striking one in nine women (one in seven in Orange County!), up from one in 30 women in 1960. Conventional estrogen replacement therapy and estrogen-based oral contraceptives have been used extensively since 1960. Clearly, an alternative is needed to provide the anti-aging and health-enhancing benefits of estrogen, while protecting against its cancer-causing effects.

Many doctors still don't believe that estrogen causes cancer, while others think that combining estrogen with a synthetic progestin neutralizes the risk. Perhaps this is based in the reports of some studies showing that estrogen does not cause cancer in the short-term. In women taking estrogen and/or a synthetic progestin for more than 10 years, there clearly appears to be a significantly elevated risk of breast, ovarian, and uterine cancers. Do you want to find out who is right?

Estrogen-progestin drugs have other well-documented side effects in addition to increased cancer risks including:

  • Weight gain
  • Abnormal blood clot formation (thrombosis)
  • Increased risk of gallstones, fibroid tumors, headaches
  • Premenstrual-type symptoms (irritability, fluid retention)
  • Thyroid metabolism impairment

One of the most popular estrogen drugs in the United States is Premarin, which contains estrogens derived from the urine of pregnant mares. Besides the fact that the process of collecting mares' urine is reportedly an inhumane and cruel procedure, the form of estrogen it produces may be the most dangerous kind. In humans, estrogen has three major forms: estrone (E1), estradiol (E2), and estriol (E3). Of the three major forms, estriol is considered to be the safest. Premarin contains no estriol. Like Cenestin, PremPro, and Premphase, Premarin is a "conjugated" estrogen, which many claim is not intended for human bodies.

Other popular estrogen drugs sold under the names Activella, Alora, Climara, Combipatch, Esclim, Estrace, Estraderm, Estring, Ortho-Prefest, Vagifem, and Vivelle contain estradiol without any estriol. While these may have advantages over the conjugated estrogens, they have not minimized the risk potential.

The question is, can the anti-aging benefits of estrogen be obtained without increasing the risk of cancer and arterial blood clots?

Estriol is used extensively in Europe for estrogen replacement therapy in menopausal and post-menopausal women and can be obtained in the U.S. from compounding pharmacies with by prescription. Evidence suggests that estriol offers many of the benefits of more traditional estrogen-replacement therapies but unlike estrone and estradiol, known as "conjugated estrogens," has not been shown to significantly increase the risk of breast and ovarian cancer when taken for more than 10 years. Estriol is secreted in huge amounts during pregnancy by the placenta to protect the fetus. In fact, urinary assay of estriol is sometimes used to assess the fetus' viability.

Since estriol is a weak estrogen, larger amounts must be used for estrogen replacement therapy compared to estradiol. One of the most common side effects of standard estrogen therapy is endometrial hyperplasia, or excessive growth of the cells of the uterine lining, a condition that can degenerate into uterine cancer. However, most investigators have found that the use of the estriol even at high doses does not cause endometrial hyperplasia.

In one study by scientists at the Medical College of Georgia, in Augusta, 52 women with severe menopausal symptoms were given estriol and had significant improvements in symptoms within one month and generally lasted as long as estriol therapy was continued. The degree of symptom improvement was directly related to the dose. It also reversed vaginal atrophy and improved the quality of cervical mucus. No breakthrough bleeding occurred in any of the subjects and biopsies of the inner mucous membrane of the uterus failed to show endometrial hyperplasia in any case, regardless of the dose of estriol used. The scientists concluded, "Estriol therapy may be employed in dosages up to 8 mg/day continuously, especially in those patients in whom other estrogens induce undesired side effects such as nausea, breakthrough bleeding, or endometrial hyperplasia, and the recurrence of hot flushes during cyclic therapy of more potent estrogens.... Being a weak estrogen, it does not induce endometrial proliferation or breakthrough bleeding of any consequence, while modifying menopausal symptoms."

A large, long-term study of estriol therapy for the symptoms of menopause conducted at the University of Ulm in Germany concluded, "Estriol therapy was successful in 92% of all cases. In 71%, hot flushes and sweating were completely eliminated, in 21% they were ameliorated, becoming weaker and occurring more seldom.... Depressive moods were abolished in 24% of the cases, and in 33% they were ameliorated, so that an overall improvement occurred in 57%." The study also found that forgetfulness, loss of concentration, irritability, and heart palpitations were remarkably improved towards normal. Also, the number of patients suffering from migraine headaches decreased from 33 to 12, and atrophying of the vulva was completely eliminated in 44 of 61 cases, and showed improvement in 12 cases. "Remarkably" the scientists added, "the quality of the skin improved according to the subjective impression of patients and physicians in a high percentage of cases. . . . In no case, did a deterioration of symptoms occur."

In China, using nylestriol (CEE), a long-acting, estriol derivative, significantly greater loss of bone mass and higher low-density lipoprotein levels occurred in 136 post-menopausal women on a placebo compared to the estriol derivative. One consideration is the use of "phytoestrogens" produced from plant sources. Phytoestrogens have been studied in great detail. For example, soy phytoestrogens have been documented to reduce hot flashes and protect against osteoporosis, heart disease, and cancer. Other plant-derived extracts have been shown to alleviate depression, anxiety, insomnia, and vaginal atrophy.

There is direct evidence from animal studies, and indirect evidence from human studies, that estriol can prevent breast cancer. Much of this work has been done by Dr. H. M. Lemon and associates of the Department of Internal Medicine at the University of Nebraska Medical Center in Omaha. In one study, they induced mammary tumors by radiation in female rats. In the control group, 75% developed tumors. However, among those animals receiving estriol, just 48% developed tumors. In another study by the Lemon team, estriol was shown to have "the most significant anti-mammary carcinogenic activity of 22 tested compounds [because] . . . estriol is less likely to induce proliferative changes in the target organs of cancer-prone women than estrone or estradiol." Lemon also found that women with breast cancer have low levels of estriol relative to other forms of estrogen.

For those who want to avoid estrogens in any form, phytoestrogens from plants are a consideration. A soy extract that provides at least 50 mg of soy phytoestrogens are often a key ingredient for effective natural estrogen replacement therapy. Based upon records of dietary soy consumption in Japan, where breast cancer incidence is very low, daily soy isoflavone intake has been estimated at 50 mg per day. The typical Western diet, on the other hand, only provides 1 to 5 mg a day of the soy isoflavones that may protect against several forms of cancer.

At a conference in Brussels, Belgium on Sept. 15-17, 1996 entitled "The Role of Soy In Medicine," there were numerous clinical studies presented showing that soy phytoestrogens in doses ranging from 40 - 160 mg a day produced rapid and significant reductions in menopausal symptoms. Other studies presented at this conference showed that, in countries where soy is a major constituent of the diet, women do not experience menopausal symptoms as do many Western.

According to peer-reviewed scientific studies, soy isoflavones protect against menopausal disorders just as FDA-approved estrogen drugs. Soy phytoestrogens have been shown to:

  • Prevent cancer at multiple sites
  • Prevent gallstones
  • Protect kidney function
  • Stimulate bone formation
  • Lower total cholesterol levels
  • Inhibit the oxidation of LDL cholesterol
  • Inhibit the development or progression of atherosclerosis

Unlike estrogen drugs, phytoestrogens have a balancing effect on the body. When estrogen levels are too low, their very mild estrogenic effects raises total estrogenic activity. When estrogen levels are too high, they compete with estrogen at cell membrane receptor sites, this lowering total estrogenic activity.

In a two month long study in the American Journal of Clinical Nutrition (1994, 60, pp. 333-340), 27 women with a mean age of 56 years had estrogenic hormonal activity and reduced hot flashes compared to placebo using 80mg of soy phytoestrogens.

At the University of Kentucky, Dr. Paolo Fanti studied the effects of genistein (from soy) on bone loss in rats without ovaries. Dr. Fanti found the mechanism of action of genistein (the most abundant soy phytoestrogen) appears to differ from that of estrogens. The protective action of genistein seems to depend on stimulation of bone formation rather than estrogen's effect of suppressing bone resorption.

A 6-month study on 66 post-menopausal women conducted at the University of Illinois at Urbana-Champaign investigated bone density and bone mineral content in response to soy therapy. The women on soy phytoestrogens showed significant increases in bone density and bone mineral content for the lumbar spine in the women compared to the control diet. Increases in bone was also found in other skeletal areas in the women on the soy diets.

A major cause of the breast cancer epidemic may be widespread use of insecticides, fungicides, manufacturing chemicals, and chlorine-based substances that mimic and mutate estrogen. These fat-soluble substances called "hormone modulating pollutants" accumulate in the body over time, and are being recognized as a contributing factor in the development of hormone-related cancers. Women with breast cancer have high levels of estrogen-altering pesticide residue in their breast fat cells compared to women who do not have breast cancer. Soy contains "friendly estrogens" that block estrogen-receptor sites on cells that are vulnerable to attack by carcinogenic "mutated" estrogens.

Kenneth D. Setchell, Ph.D. of Children's Hospital and Medical Center in Cincinnati, Ohio confirmed the estrogenic activity of the principle soy isoflavones daidzein, genistein, and glycitein. Dr. Setchell then conducted research on the chemical structure and metabolism of soy phytoestrogens, and concluded that consuming modest amounts of soy protein results in relatively high blood concentrations of phytoestrogens and that this could have a significant hormonal effect in many individuals.

One of the reasons estrogen replacement therapy may be effective in helping to reduce the risk of coronary heart disease in post-menopausal women may be due in part to its antioxidant properties. Considering the increased risk of breast cancer and uterine cancer in women using estrogen drugs, the researcher suggested that one alternative is to take phytoestrogens, such as genistein, which has been shown to protect the heart against cardiovascular disease. In studies using female monkeys who had their ovaries removed to simulate post-menopausal women, it was shown that genistein inhibited LDL (the harmful form of cholesterol) oxidation by 48%. When used in combination with vitamin E this effect was even more pronounced!

An important and widely-studied plant component used to treat menopause is a standardized extract from the Black Cohosh plant also known as Cimicufuga racemosa. This black Cohosh extract is approved by the German Ministry of Health for the treatment of menopausal symptoms related to estrogen deficiency. Standardized black Cohosh has been trademarked under the name Remifemin for sale as a drug in countries throughout then world. More than 1.7 million women in Europe and Australia have used this natural herbal extract to treat menopausal symptoms. Clinical studies show that Remifemin not only alleviates hot flashes, but also depression, anxiety, vaginal atrophy, and a host of other menopausal-related disorders.

A German study (Med Welt, 1984, 36, pp. 871-874) involved 60 women given either standardized black Cohosh extract, Valium, or Premarin (synthetic estrogen) for menopausal symptoms. The women in the black Cohosh group were relieved of depression and anxiety more effectively than the women in the Valium or Premarin group! European women have been using black Cohosh for decades as a safer alternative to estrogen replacement.

Another 6 month study published in the German journal, Zent bl. Gynakol. (1988, 110, pp. 611-618) on black Cohosh extract involved women under age 40 whose ovaries had been removed. One group received estriol (E3), the second group received Premarin, the third took Premarin and a progestin drug, the fourth was given black Cohosh extract, and the fifth group received a placebo. The results of the study showed that women experienced a 30% improvement hot flashes, irritability, heart palpitations, etc. in all groups receiving different forms of estrogen-progestin and black Cohosh extract. There was no improvement in the placebo group. At the conclusion of the study, the majority of women receiving the estrogen drugs or black Cohosh extract were symptom free. However, the women receiving the black Cohosh extract reported fewer side effects.

The most impressive study on the benefits of black Cohosh extract was done by 131 physicians on 629 menopausal women (Gynecology, 1, 1982 14-16). This study showed that produced clear improvement in both physical and psychological symptoms in over 80% of patients within 6 to 8 weeks. Here were the results of the changes in specific menopausal symptoms:

Symptom

Women who became symptom free

Women who improved

Hot Flashes

43.3%

86.6%

Profuse perspiration

49.9%

88.5%

Headache

45.7%

81.9%

Vertigo

51.6%

86.8%

Heart palpitation

54.6%

90.4%

Tinnitus

54.8%

92.9%

Nervousness/irritability

42.4%

85.6%

Sleep disturbances

46.1%

76.8%

Depressive moods

46%

82.5%

Most patients in the above clinical study reported noticeable benefits within 4 weeks. After 6 to 8 weeks, complete resolution of symptoms was reported in a high number of patients.

A placebo-controlled study published in the German journal, Planta Med., 57 (1991) investigated the mechanisms by which black Cohosh helps menopausal symptoms. Hot flashes correspond closely with a surge of luteinizing hormone (LH) released from the pituitary gland in response to estrogen deficiency. Black Cohosh was shown to suppress increased luteinizing hormone secretion in menopausal women and this effect was specifically linked with a reduction in the incidence of hot flashes.

Black Cohosh extract does not elevate estradiol levels in the blood, rather it appears to bind to estrogen receptors and mimic a weak estrogen, estriol (E3). Estriol has been shown to be protective against the cancers that more potent forms of estrogen (estradiol and estrone) appear to cause. Black Cohosh extract has been referred to as being "estriol-like", because of the rejuvenating effect it exerts on the vaginal, rather than the uterine lining. Because of the impressive safety record of standardized black Cohosh extract, it is has become a popular natural alternative to FDA-approved estrogen drugs.

An extract from the licorice root called glycyrrhetic acid (GA) stimulates the natural conversion of testosterone to estrogen in the body. Glycyrrhetic acid is also an antioxidant, liver protectant, viral activity suppressant in hepatitis patients, immune function modulator, cancer cell replication suppressor, and clotting factor (thrombin) inhibitor. Not only have numerous studies indicate that Glycyrrhetic acid is an effective estrogen replacement option, the Chinese have successfully used licorice extracts for more than 3,000 years to treat menopausal disorders.

Dong Quai (also called Tang Kieu) is often used as a female tonic in traditional Chinese medicine. It has been used successfully to alleviate PMS (premenstrual syndrome) and menopausal symptoms by helping to normalize estrogen levels. Dong Quai extract has shown to have a muscle relaxant effect, and has been used as an analgesic and anti-inflammatory agent. Scientists believe that one unique mechanism of action of Don Quai is to promote natural progesterone synthesis. Progesterone, which will be discussed in more detail below, is actually more important than estrogen for preventing and treating osteoporosis because progesterone is directly involved in the production of bone-forming cells called osteoblasts.

Another hormone imbalance that some women encounter as they grow older is excessive prolactin secretion from the pituitary gland. Prolactin interferes with the beneficial effect of estrogen and may promote the development of estrogen-induced cancers. Prolactin secretion may be suppressed by a natural extract called Vitex agnus castus, which also promotes progesterone synthesis (Arzneim. Forsch./Drug Res., (43 (II), 7, 1993). As with the other plant hormone modulating extracts, side effects are not often observed. It should be noted that prolactin is so dangerous in patients with hormone-dependent cancers, that prolactin suppression drug therapy is often suggested for breast and prostate cancer patients.

From about the age of 30, women gradually produce less progesterone. This decline becomes significant as women get closer to menopause. Symptoms of a progesterone deficit include pre-menstrual discomfort, night sweats and hot flashes, along with a loss of the sense of well-being (depressed feelings). Scientific studies indicate that progesterone may help prevent breast cancer in part through activation of natural killer cells and through diminishing the production of a cancer-promoting form of estrogen called 4-hydroxyestrone while increasing the production of cancer-preventing estriol mentioned above. In other words, estrogen may be made safer through when taken with progesterone. In addition, progesterone may help to prevent the mental decline that occurs with aging. Progesterone has been shown to increase neuronal energy production and to protect brain cells.

Interestingly, the combined effects of these two critical hormones lead to the prevention of bone loss at all ages, though progesterone deficiencies appear to be more significant a factor as women age. There are two types of bone regulating cells. The osteoclasts function to dissolve older bone and leave tiny unfilled spaces behind. The osteoblasts then move into these spaces and produce new bone. This process of dissolving older bone mass by osteoclasts and new bone formation by osteoblasts is the mechanism for the repair and continuing strength of bone.

Like all living cells, osteoblasts and osteoclasts require hormonal guidance to properly function. Osteoblasts depend primarily on progesterone and testosterone, while osteoclasts need estrogen-like hormones. In the absence of these hormones, osteoblasts and osteoclasts cease to function properly and rapid deterioration of the bone occurs. Osteoporosis can occur when osteoclasts dissolve more bone than what the osteoblasts are able to replace.

Estrogen regulates the activity off osteoclasts, which results in a slowing of dissolving older bone. Progesterone, on the other hand, promotes the production of osteoblasts which are required to effect new bone formation. Natural progesterone has been shown to stimulate the new bone formation required to prevent and reverse osteoporosis.

Although osteoporosis can be caused by mineral and vitamin deficiencies, corticosteroids, drugs, poor eating habits, lack of exercise, too much cortisol, and too little testosterone (two other important hormones), the major influence on age-associated bone deterioration, however, is often a deficiency of progesterone.

Natural progesterone cream is often prescribed to help prevent osteoporosis, menopausal symptoms, depressed feelings, and breast cancer. Several recent studies indicate that topically applied progesterone cream works better than what was originally published. There is an ongoing FDA-approved clinical study entitled, "Use of Natural Progesterone Cream in the Prevention of Osteoporosis: A Randomized Double-Blind Placebo Controlled Trial." The women being studied are 1-5 years postmenopausal, which is when bone loss is most rapid. After the first year, the positive effects of progesterone became so apparent, that the doctors could tell which women were receiving progesterone compared to the placebo even the they did not know who received the progesterone or the placebo. The women in the progesterone group experienced the disappearance of lumps and bumps in their breasts, were less depressed, had fewer hot flashes, and better bone densities (though the time interval was too short for this to be significant). None of the women using progesterone cream lost bone density, while the placebo group showed slight bone loss. The expectation is that the women on the progesterone will have significantly greater bone density compared to the placebo.

Research also indicates progesterone may help prevent mental decline in the elderly. John Lee, M.D. one of the worlds' foremost experts on progesterone therapy, has found studies showing that the brain cells concentrate progesterone 20 times greater than blood serum levels. Recovery after brain trauma is better if progesterone levels are higher. Dr. Lee also has pointed out that progesterone has been shown to increase brain cell energy production while suppressing hyper-excitotoxicity. "Excitotoxicity" occurs when too much (or too little) of neurotransmitters such as glutamate are released from brain cells. This type of toxicity is now considered a cause of brain aging and degenerative neurological disease. It appears that progesterone protects against this type of brain cell damage.

There is evidence suggesting that progesterone is not only protective against but also a potential treatment for breast cancer (Cowan, 1981; Hagen, 1998.) A study by Chang (1995) showed transdermal estradiol increased 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. More evidence confirming progesterone-protective effects on breast tissue comes from a study by J.M. Foidart in Fertility and Sterility (April, 1998.) Either 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 and it was found that estradiol increased breast cell proliferation and that progesterone greatly decreased proliferation. This is direct evidence that estradiol (a potent estrogen) stimulates hyper-proliferation of breast tissue cells and progesterone prevents hyper-proliferation.

Retrospective studies have shown that women undergoing breast cancer operations 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. P.E. Mohr in the British Journal of Cancer (1996) reported that women with a progesterone level of 4 mg/ml or more at the time of their breast cancer surgery, 65% survived 18 years compared with 35% survival of those with a lower serum level of progesterone. In a study done by Cowan et al. in 1981, published in the American Journal of Epidemiology, it was shown that the incidence of breast cancer was 5.4 times greater in women with low progesterone than in women who had good progesterone levels.

Testing progesterone levels is important, especially for pre-menopausal women who are using progesterone cream to alleviate pre-menstrual syndrome (PMS) symptoms. In women taking estrogen, adding progesterone may enable the dose of estrogen to be reduced, since progesterone restores sensitivity to estrogen receptors on cell membranes. The method of testing progesterone requires a separate discussion since saliva levels, blood levels, and urine levels all have limitations.

The issue of synthetic versus natural hormones is never more important than it is with progesterone, synthetic progestins do not act at all like progesterone and are termed as "progestins." The most common progestin is Provera, which list of side effects include possible birth defects, breast cancer, blood clots, fluid retention, acne, rashes, weight gain and depression.

In contrast to artificial progestins, real progesterone is often derived from soybeans or wild-yams. Unfortunately women cannot simply eat wild yams or wild yam products. The human body does not have the means of converting these plants into progesterone molecules. Progesterone, made from any source, is easily utilized as it is identical to the progesterone manufactured within the human body. Progesterone are available as creams that are rubbed in to the skin which bypasses the liver and allows better hormone delivery to the tissues. For example, progesterone cream applied to the breasts slows cell proliferation and often eases breast pain. As to safety, according to Northrup, (1994) "There is virtually no danger of overdose."

Prometrium® is a brand of progesterone that is available at every pharmacy by prescription. It comes as an oral capsule containing either 100 mg or 200 mg of natural progesterone. Compounding pharmacies can make other strengths of progesterone for oral use. Most progesterone taken orally is metabolized by the liver and thus will be unavailable for cellular use. Although the progesterone cream is reportedly better utilized and more economical due to avoiding the "first passage effect" through liver, either form of progesterone is effective in clinical practice. Injectable progesterone in oil is also available and is typically given once every several weeks.

DHEA (dehydroepiandrosterone) is a precursor of estrogen and testosterone, so taking DHEA may raise the levels of these hormones. While there have been contradictions in the research on DHEA, it can be rejuvenative to at least a moderate degree for the right person, improving mood, neurological functions, immune system functioning, bone growth, energy, and feelings of well-being. In Endocrine News (1996), DHEA was given until the patient's blood levels matched those found in their teenage years. The journal reported "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." Because DHEA may raise estrogen levels, safeguards against excessive breast cell proliferation should be considered.

Both men and women's levels of DHEA declines 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 and Morganthaler, 1997.) As with all hormones, blood levels are only one criterion to establish in supplementation. The ultimate goal is individual functioning.

Hormone Imbalances Affect All Ages

While the discussion of hormones usually occurs around menopause, there are many health problems caused by hormonal imbalances well before the age of menopause. Hormonal dysfunctions are found to be the cause of many menstrual complaints, the most prominent being premenstrual syndrome (PMS). The complex hormonal interactions required to produce a "normal" menstrual cycle are easily disturbed by a variety of biochemical, environmental, and psychological sources. Most women with PMS tend to have relatively high levels of estrogen and relatively low levels of progesterone. Other factors associated with PMS are diet, obesity, vitamin-mineral deficiencies, and an imbalance in hormone-like compounds called eicosanoids.

Painful uterine menstrual cramps, like PMS, are often treated with birth control pills (hormones) to eliminate the ovulation-related hormonal changes that lead to cramping. Since excess prostaglandin production causes contractions of the smooth muscles, another treatment is to use medications that inhibit prostaglandins (Advil Aleve, Anaprox, etc.). Prostaglandins are chemicals that regulate involuntary muscles: blood vessels, uterus, and intestines. They are a form of eicosanoids derived from essential fatty acids.

Irregular menstrual bleeding can also have a hormonal basis. Irregular menses or bleeds (spots) between periods, excessive menstrual bleeding, and other forms of "dysfunctional uterine bleeding" are frequently due to an estrogen-progesterone imbalance, though thyroid or pituitary problems are other possible causes. In its most severe forms, heavy menstrual bleeding can lead to anemia, requiring nutritional supplements just for that deficit alone. Treatment may include raising progesterone levels and taking prostaglandin inhibitors to decrease the flow of blood forced out by uterine contractions.

Breast pain can also come from the hormonal changes of the menstrual cycle. Breast tissue is affected by cyclic change, just like the uterus. Alterations in hormones such estrogen, progesterone, and prolactin (a hormone whose function is to stimulate lactation) have been implicated. Of the most concern is that breast tissue is extremely sensitive to estrogen. High estrogen levels lead to tissue growth, cyst formation, and pain (as well as cancer). Because progesterone balances estrogen by "down-regulating" the estrogen receptor cells in the breast, it blocks estrogen's "grow" signals. The result is to decrease the proliferation of cell tissues, protecting them from the dangerous, negative effects of even modest amounts of estrogen.

Excessive Sex Hormones Cause Excessive Tissue Growth

Benign fibroid uterine tumors are the number one reason for hysterectomies in the United States (Hutchins, 1990.) Their cause is unknown and they often prove asymptomatic, depending on their size and location. Typically, fibroids shrink after menopause because of the reduction in estrogen. Remember, estrogen is a growth-stimulating hormone. Some fibroids may be managed with progesterone.

Polycystic ovaries is a condition directly caused by a hormone imbalance. Because of an excess of androgens (the "male" hormones), normal egg development is prevented. When eggs are underdeveloped, numerous, small cysts are formed. Standard medical treatment includes prescription birth control pills, anti-androgenic medications, or synthetic progestin to prevent the uterine lining from suffering from excessive hormonal stimulation. Alternatively, natural progesterone may reduce symptoms because low dose progesterone reduced androgens.

Another tissue-growth health concern is endometrial hyperplasia, an excess of glandular tissue in the uterine lining. This condition is most common in women with irregular periods, irregular egg production, and irregular sloughing of the lining of the uterus. Although usually no further degerenation of the tissue occurs, it is necessary to make sure that abnormal cells are not present and that the condition does not become chronic. Traditional treatment involves giving a synthetic progesterone such as Provera to cause the uterine lining to slough off, removing the excess tissues. If this fails, a D and C (dilation and curettage) maybe performed. Again, progesterone can decrease estrogen receptor cells and resolving the problem. Endometrial overgrowth is why progesterone or progestins must be used in women who have a uterus.

Endometriosis describes a condition involving the migration of endometrial tissue to other areas of the body, typically within the pelvis (but occasionally even further away from its point of origin.) It may lead to pelvic pain, menstrual dysfunction, bowel pain or infertility. Endometriosis is hormone-dependent, involving high levels of estrogen. Birth control pills, synthetic progesterone, or drugs such as Lupron, which make a woman temporarily menopausal are used to reduce the level of estrogen leading to a drop in "grow" signals to the endometrial tissues.

As you can see, the primary focus is on the balance of estrogen and progesterone. While the breasts and uterus are saturated with estrogen receptor cells, the presence of sufficient progesterone "down-regulates" such receptors, protecting against the powerful "grow" signals of estrogen. In addition, a compound called I3C (indole-3-carbinol) affects estrogen metabolism in ways that reduce the risk of breast cancer (Telang et al., 1997.) Broccoli, cauliflower and other cruciferous vegetables contain I3C and related compounds. There are also nutritional products containing I3C product in pill form.

Cancer

Women born with a gene labeled "BRCA 1" have a significantly increased risk of breast cancer because the gene causes an excessive ovarian production of estrogen (Stratton et al., 1997.) Certain types of estrogen stimulate breast cancer cells.

Although the cause of ovarian cancer is far less evident than breast cancer, hormones do have a role. Helizisouer et al., (1995 ) discovered a strong connection between ovarian cancer and androgens. Women taking involves birth control pills have a lower risk of getting ovarian cancer, possibly because of the decrease in ovarian stimulation. Conversely, fertility drugs increase ovarian activity and are linked to higher rates of ovarian cancer.

The most important fact about uterine cancer is straightforward and the same as in the previous forms of malignancies: estrogen encourages the growth of uterine tissue.

Lack of Sex drive (Libido) is not just psychological

The loss of sexual desire is far more common in women of all ages than is recognized, largely because of the cultural and societal pressure on women, and the lack of communication with their physician. Certainly there can be psychological and./or relationship issues involved, hormones play a significant and often undiscovered role.

Davis (1998) points out that while using androgens with postmenopausal women successfully increases their sexual desire, the bigger picture is that androgen levels fall significantly throughout the reproductive years and probably affect desire from an early age. In addition, Braunstein reported in a Reuters Health news release that transdermal testosterone increased women's perception of orgasmic pleasure. Some androgens in particular (DHEA and DHEA sulfate) 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 in conjunction with progesterone (Slayden, 1998.) Many women lose their sexual desires after giving birth. Many of these sexual problems are directly tied to general postpartum depression. Balancing estrogen and progesterone can reduce many negative postpartum outcomes including loss of libido. Serotonin also influences libido and improving serotonin levels are often successful.

Alzheimer's and Hormone Deficits

There is some evidence that estrogen may protect against Alzheimer's because those women with the highest estrogen levels have the lowest rate of Alzheimer's (Northrup, 1998.) Estrogen, DHEA and pregnenolone increase connections among brain cells, and enhance memory (Flood et al., 1992.) Wright and Morganthaler (1997), in their book Natural Hormone Replacement, recommend hormone replacement to help prevent senility and Alzheimer's disease. These researchers also emphasize the significant differences between synthetic and natural hormones, both in safety and effectiveness.

Hormone Modulation

Achieving proper hormonal balance is not a one-step procedure. Individualization offers the greatest amount of long term health improvement and is based on testing and feedback. Adjustments only can be achieved by self-evaluation and testing before and after hormone-affecting supplements are taken. Testing may be performed in several ways:

Blood measurements have the advantage of widespread established technology and standards, plus the universal coverage by insurance carriers. However, different labs have different standards. One lab's standards 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.

Saliva measurements does not have the standards or medical community endorsement that blood testing enjoys, but it is available by mail order and offers a degree of convenience. Most insurance companies will not pay for it. 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. I have not been satisfied with the results of saliva profiles. They don't seem to correspond well with what the patient is telling me.

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 and Morganthaler, 1997). By collecting a full day's worth of urine, a woman gets a more complete picture of her actual levels. The shortcoming of this test is the difficulty involved in its collection: every drop of urine must be gathered during the 24-hour period. It is relatively expensive but a full spectrum of hormones and their metabolites can be tested from one sample.

Successful Management

The key to success is listening to your symptoms, being patient and observant, and monitoring the appropriate hormone profiles. 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? Is it more important to use only plant hormone sources or to change blood hormone levels back to those of a younger age? These are the types of decisions to be made by each woman.

A "priming" program based on the "cascade" effects of DHEA as it gradually converts into all of the other hormones has been suggested by the Life Extension Foundation. To protect against the possible over-conversion to estrogen, melatonin and soy extracts are included as a cancer safeguard. This program may balance hormones back to the desired levels and eliminate any symptoms. If this does not occur, more specific recommendations may be necessary. Remember, wait 45 days before testing to determine the effect of each new supplement or new supplement dose.

Women already taking estrogen drugs such as Premarin can often wean themselves off the synthetic hormones over several months as follows using various hormone or phytonutrients alternated every other day with the prescription medication on the every other day for one month. The 2nd month, the replacement is used two days in a row and the prescription medication for one day every third day. The 3rd month, the replacement is used 3 days in a row and the previous medication one day every fourth day.

If estrogen is chosen and indicated, Estriol (E3) is considered the safer form of estrogen and is typically prescribed at 2 and 8 mg per day, based on the ratio of 2 mg of estriol to 0.625 mg of Premarin. Again, trying and evaluating different dosages is the way to achieve the important goal of taking the least amount of estrogen that attains the desired blood or symptom level. Estriol creams in varying potencies may be tried for localized problems like vaginal dryness and thinning.

If estriol alone not achieve a woman's goal, the next step is the utilization of a compound estrogen drug such as Bi-Est or Tri-Est, the medication described earlier as having three forms of estrogen in the same proportion found in human females. Typically, women are prescribed 1.25 mg of estriol twice daily for mild menopausal symptoms. Stronger symptoms may require double the dosage. If Tri Est is not adequate, it is possible to have a cooperative physician order individualized estrogen mixtures from formulary pharmacies. In this way, if the Tri Est with only 20% of the more dangerous estradiol fails to alleviate symptoms, a drug may be made with 40 or 60% estradiol. This is still a better choice than the standard medications with 80% estradiol. This graduated protocol is appropriate for any situation requiring supplemental estrogen.

For progesterone supplementation or repletion, natural progesterone is more beneficial than synthetic "progestin" drugs. Natural progesterone can be delivered through the skin in the form of transdermal creams and are extremely safe. This route of administration bypasses the liver and allows hormone delivery to the place where it is needed the most. The cream should be massaged into soft tissue areas such as breasts, underarms, and inner thighs on a rotating basis to avoid the over-saturation of cells. Overdoses of progesterone have not been reported. Nipple tenderness if too large a dose of progesterone is applied. Progesterone is usually taken at night since it helps promote sleep and drowsiness or many people. The time of the month it is used depends on whether it used for PMS or for estrogen balance in menopause.

Since DHEA, like progesterone, is a precursor of estrogen and testosterone, taking it might raise the levels of both of these hormones. Like progesterone, DHEA is a good starting place for hormone modulation because of this ability, and many woman find both hormones will rise to more youthful levels by supplementing DHEA alone. Women seem to do better using DHEA twice a day in dosages up to 25 mg twice daily. On a cautionary note, women with reproductive cancers should not take DHEA. In fact any woman with a family history of ovarian cancer, or a high score on an ovarian cancer blood screening test known as CA 125, should avoid all androgen supplements.

If there is adequate symptom improvement, blood levels of DHEA (unconjugated and the sulfated storage form) should be performed to monitor for excess DHEA. Blood levels considered ideal would be the level that is normal for a 20 to 30-year old woman (Yen, 1990).

Every hormone is influenced by both environmental and nutritional factors. Here are some of the most important of these factors:

  1. Stress. There are strong correlations between excessive stress and such problems as adrenal insufficiency, lack of menstrual cycle, PMS, vaginitis, urinary incontinence, bone loss and infertility.
  2. Smoking. Obviously, the link between cancer and smoking is well documented. Less well known is smoking's connection to bone loss, cervical dysplasia , miscarriage and Alzheimer's Disease.
  3. Exercise. The obvious connection here is to osteoporosis. But lack of regular exercise plays a role in adrenal disease, cardiopulmonary disorders, loss of libido, and menstrual problems.
  4. Obesity. Some menstrual disorders are found more often in overweight women. In fact, a diet that lowers body fat may lower estrogen levels as well.
  5. Nutrition. Here are some areas in which dietary supplements play an important role in the development and treatment of hormonally related diseases:
    • Research at Johns Hopkins Medical School demonstrated 600 IUs per day of vitamin E raised both estriol and progesterone levels in a group of women with fibroid breast disease. Both estriol and progesterone help to protect against estrogen's possible tumor-creating effects.
    • Adequate calcium, magnesium vitamin D3, and other trace minerals (as outlined in my webpage on osteoporosis.
    • Antioxidants as vitamin C, vitamin E, CoQ10, bioflavonoids, proanthocyanidins, alpha-lipoic acid, etc. may be of great assistance including benefits on cardiac problems and cancers.
    • Diets high in processed and saturated fats lead to heart disease, cancers, and an imbalance in the eicosanoid hormones (an important factor in fibroid cysts.) In contrast, diets high in essential fatty acids help to balance eicosanoids. Other eicosanoid imbalance links include uterine cramps, pelvic pain, and breast pain.
    • Various vitamins have been examined by researchers. Abraham (1983) found vitamin B6 to be helpful in reducing menstrual cramps. More recently, Mills (1996) showed that supplementing the B complex group in women with endometriosis produced a significant decrease in symptoms.
    • Bioflavonoids appear to actually inhibit excessive estrogen synthesis (Kellis and Vickery, 1984.)

Summary

Beyond the well-publicized hormone replacement therapy for menopausal symptoms, such disorders as PMS, endometriosis, several types of cancer, sexual dysfunctions, fibroid tumors, osteoporosis, cardiac disease, and Alzheimer's Disease are closely related to hormonal imbalances. Many disorders are linked to either excessive or deficient estrogen levels, particularly as they compare to the amount of progesterone available. Not only should hormones be modulated regularly, but natural sources for hormone balance should be considered. Synthetic and non-human analogue hormones may carry side effects that do not occur with appropriate replacement and balancing programs. Hormone modulation requires individualization, and works best when carefully monitored through laboratory testing. Both lifestyle and nutritional variables play an important role in hormone modulation.

Estrogen is an anti-aging hormone that provides many beneficial effects throughout the body. The major drawback to estrogen therapy is the increased risk of certain cancers. FDA-approved estrogen drugs have other adverse side effects that preclude many women from effectively using them. Natural plant extracts provide the body with safe and possibly more effective estrogen replacement.

Menopause is not just an estrogen deficiency. Numerous hormone imbalances threaten the health of menopausal women. The published literature has identified several plant extracts that favorably modulate hormone balance in aging women.

The decline in progesterone production is correlated with increased bone loss and increased risk of cancer. Many of the effects associated with normal aging can be attributed to a progesterone deficiency. The beneficial effects of natural progesterone have now been shown in women and men. It usually takes two to four weeks for topically applied progesterone to build up to sufficient levels in the body to the point of noticeable effects.

Individual symptomatic improvement and blood analysis of estrogen, progesterone, testosterone, prolactin, luteinizing hormone, and follicular stimulating hormone (FSH) can help determine how well natural hormone modulation therapy is working.

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Jeremy E. Kaslow, MD, FACP, FACAAI Physician and Surgeon
Board Certified Internal Medicine

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