~Female Hormone Modulation, Part 2

Ipriflavone and Bone Loss

Early reports on the synthetic isoflavone known as ipriflavone were positive for the prevention of bone loss, certainly in early menopause. This synthetic isoflavone is synthesized from daidzein and has generated considerable interest in the hormone and bone loss research community (Gennari et al. 1998). A 2-year trial tested women of postmenopausal age of less than 5 years who had low vertebral bone density: 56 women received 200 mg, of ipriflavone three times a day, with meals or a placebo. All subjects received 1 gram of oral elemental calcium daily. After 2 years, vertebral bone density did not change in those receiving ipriflavone. By comparison, women receiving the calcium showed limited bone loss during the treatment.

In another 2-year study, 198 postmenopausal women (50-65 years of age) were randomly allocated to treatment with oral ipriflavone or a matching placebo according to a double-blind, parallel group design. All subjects also received 1 gram of calcium carbonate. The ipriflavone-treated women showed a significant increase of vertebral bone density at the end of the treatment period. The placebo group presented a significant decrease of vertebral bone density. In addition, urinary HOP/Cr, a measure of bone loss, was significantly decreased, suggesting a reduction in bone turnover rate. There was also a reduction in the incidence of vertebral fractures in the ipriflavone-treated group as compared to placebo (Agnusdei et al. 1997a).

In another multicenter, double-blind, 2-year study, 149 elderly, osteoporotic women (65-79 years of age) with prevalent vertebral fractures were randomly allocated to receive either ipriflavone or matching placebo, plus 1 gram of oral calcium daily. A significant increase in forearm bone mineral density (measured by dual photon absorptiometry) was obtained after ipriflavone treatment. The placebo group showed only limited bone loss, probably due to the calcium supplement. In addition, urinary hydroxyproline, a measure of bone loss, was significantly decreased in the ipriflavone-treated group, suggesting a reduction in bone turnover rate. There was also a reduction in the incidence of vertebral fractures in the ipriflavone-treated group as compared to placebo (Agnusdei et al. 1997b).

These authors also stated that almost 3000 patients had been treated with ipriflavone, for a total of over 3000 patient-years, in 60 clinical studies from over 3 countries. The incidence of adverse reactions in the ipriflavone-treated patients was similar to that observed in subjects receiving placebo, suggesting that long-term treatment with ipriflavone may be considered safe, may increase bone density, and may possibly prevent fractures in elderly patients with established osteoporosis (Agnusdei et al. 1997b).

Halpner et al. (2000) found that urinary N-linked teleopeptides, another marker of bone breakdown, declined by 29% in those receiving ipriflavone supplement. Nozaki et al. (1998), at the Department of Gynecology and Obstetrics (Kyushu University, Japan), tested conjugated estrogens and ipriflavone together. They reported that in ovariectomized women, bone mineral density was reduced 48 weeks after treatment by the use of placebo, conjugated estrogen alone, and ipriflavone alone. However, a combination of conjugated estrogen and ipriflavone resulted in much less bone loss following ovariectomy. This purpose of using a potent estrogen drug and ipriflavone was to prevent acute short term bone loss following ovariactomy.

Contrary to the majority of trials, the most recent large-scale trial, with 474 postmenopausal osteoporotic participants, showed no changes over placebo in terms of bone loss or biochemical markers of bone metabolism. This group also found that ipriflavone caused lymphocytopenia (decrease in the number of immune lymphocytes) in a significant number of women, although this appeared to be reversible. This latter side effect has not been reported before and could represent a significant negative factor in considering treatment (Alexandersen et al. 2001).

Currently, the research on ipriflavone is in the early stages and further studies are warranted before considering ipriflavone in terms of alternatives or adjuncts to other hormonal treatments for the purpose of preventing bone loss.

Black Cohosh Alleviates Menopausal Discomforts

An important and widely studied plant component used to treat menopause is a standardized extract from the black cohosh plant, which is also known as Cimicu-fuga racemosa. This black cohosh extract is approved by the German Ministry of Health (The German Komission E) 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 the 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 alleviates not only hot flashes, but also depression, anxiety, vaginal atrophy, and a host of other menopause-related disorders (Liske 1998).

A fascinating early study involved 60 women who were given standardized black cohosh extract, Valium, or Premarin (synthetic estrogen) for menopausal symptoms. The women in the black cohosh group were relieved of their depression and anxiety more effectively than the women in the Valium or Premarin groups (Warnecke 1985).

Another early study of black cohosh extract involved women under age 40 who produced very little natural estrogen or progesterone because their ovaries had been removed by hysterectomy. One group received estriol (a weak, but safer form of estrogen); the second group received Premarin; the third took Premarin and a progestin drug; the fourth group was given black cohosh extract; and the fifth group received a placebo. This 24-week study rated the women according to symptoms, including hot flashes, irritability, heart palpitations, etc. The results of the study demonstrated that women in all groups receiving different forms of estrogen-progestin and black cohosh extract experienced a 30% improvement. No improvement was seen 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. Most importantly, the women receiving the black cohosh extract reported fewer side effects. This study showed that phytotherapy with standardized black cohosh worked as well as estrogen drugs, but produced fewer uncomfortable and dangerous side effects (Lehmann-Willenbrock et al. 1988).

The most impressive early study on black cohosh was carried out by 131 physicians in 629 menopausal women. This study demonstrated that black cohosh extract produced clear improvement in over 80% of patients within 6-8 weeks. Both physical and psychological symptoms improved. The results of the changes in specific menopausal symptoms appear in the following table:
SymptomPercent who became symptom-freePercent who showed improvement
Hot flashes43.386.6
Profuse perspiration49.988.5
Heart palpitation54.690.4
Sleep disturbances46.176.8
Depressive moods46.082.5

Most patients in this clinical study reported noticeable benefits within 4 weeks. After 6-8 weeks, complete resolution of symptoms was reported in a high number of patients (Stolze 1982).

A placebo-controlled study by Duker et al. (1991) investigated the hormonal mechanisms by which black cohosh alleviates menopausal symptoms. The physicians conducting the study pointed out that hot flashes correspond closely with a surge of luteinizing hormone (LH) released from the pituitary gland in response to estrogen deficiency. The weak estrogen-like effects of black cohosh suppressed increased luteinizing hormone secretion in menopausal women, and this effect was specifically linked with a reduction in the incidence of hot flashes (Duker et al. 1991).

Black cohosh extract has shown estrogenic effects within the body in several studies, but it does not elevate estrogen levels in the blood. Black cohosh extract appears to bind to estrogen receptors in order to mimic the hormonal effects of the weak estrogen, estriol. Estriol is a weak estrogen that has been shown to protect against the types of 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. However, this weak estriol-like effect of black cohosh has not been shown to have a significant effect on bone density. Because bone density decreases substantially during the first 7 years after occurrence of menopause, osteoporosis is one of the long-term risk factors resulting from a prolonged deficiency of hormones and an imbalance of these hormones in the menopausal and postmenopausal period.

Liske (1998) states that black cohosh shows good therapeutic efficacy and tolerability profiles. Because of the impressive safety record of standardized black cohosh extract, it is has become a popular natural alternative to FDA-approved estrogen drugs. However, this phytoestrogen has not demonstrated any significant effect on the prevention of osteoporosis. It therefore should be used in conjunction with other agents that protect against bone loss.

More Estrogenic Plants
  • Licorice Root Extract
  • Dong Quai
  • Vitex Extract
There are other, important, plant-derived hormone modulators that are used by alternative physicians to treat menopausal symptoms. It is important to understand that estrogens are continually being modified as they circulate in the body. They are converted from one form to another and are outfitted with numerous other compounds that cause their biological activity to vary considerably. While it may appear that the combination of soy phytoestrogens and standardized black cohosh may provide complete estrogen replacement, there are other hormonal factors to adjust for if the metabolism of youth is to be maintained (or restored).

Licorice Root Extract

An extract from the licorice root called glycyrrhetic acid (GA) stimulates the natural conversion of testosterone to estrogen in the body (Takeuchi 1988). Glycyrrhetic acid is an antioxidant that is often used to protect the liver and suppress viral activity in hepatitis patients (Abe et al. 1994). Some alternative cancer clinics prescribe high doses of GA in injectable form to patients because of studies showing that GA modulates immune function and suppresses cancer cell replication. It is interesting to note that while FDA-approved estrogen drugs can cause abnormal blood clotting, the GA contained in licorice root inhibits the clotting factor thrombin (Francischetti et al. 1997), thus reducing the risk of a heart attack or stroke. Licorice root extracts have many disease-fighting applications, but for menopausal women, the most important factor is that glycyrrhetic acid extracted from licorice is a safe source of natural estrogen (Rafi et al. 2000; Tamir et al. 2000). Numerous studies indicate that GA is an effective estrogen replacement therapy in humans, and the Chinese have successfully used licorice extracts for more than 3000 years to treat menopausal disorders.

Dong Quai

Dong Quai extract is a female tonic in traditional Chinese medicine. It has been used successfully to alleviate PMS (premenstrual syndrome) and menopausal symptoms (Hardy 2000). Dong Quai extract has been shown to have a muscle relaxant effect and has been used as an analgesic and anti-inflammatory agent. Scientists believe that one mechanism of action of Dong Quai is to promote natural progesterone synthesis. Progesterone (to be discussed in more detail later) is another hormone whose production declines at menopause.

Progesterone may be more important than estrogen for preventing and treating osteoporosis because progesterone is directly involved in the production of bone-forming cells called osteoblasts. Many menopausal women use a topical natural progesterone cream to provide for direct absorption of progesterone into the bloodstream. Beware of commercial Dong Quai root supplements that contain too much active ingredient (i.e., 250-535 mg of Dong Quai per capsule). This dose is too high and not necessary when taking other hormone-modulating plant extracts such as black cohosh, soy phytoestrogens, glycyrrhetic acid, etc. because it can be toxic. A balanced herbal formula should not contain more than 50 mg of Dong Quai in the recommended daily dose.

Vitex Extract

Another hormone imbalance that 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. The clinical symptom of excessive prolactin secretion is a modest amount of breast milk production in a non-pregnant woman, noted by a milky discharge from the nipples of the breast (galactorrhea). The diagnosis is confirmed by a serum blood test for prolactin which may be followed by a brain scan in search of a prolactin secreting adenoma (tumor) of the pituitary gland.

Prolactin secretion may be suppressed by a natural extract called vitex agnus castus (Chaste tree berry). In a study by Milewicz et al. (1993), vitex agnus castus extract (abbreviated as vitex) was shown to suppress excessive prolactin secretion and promote natural progesterone synthesis over a 3-month period. As with the other plant hormone-modulating extracts, no side effects were observed. Vitex acts on the pituitary gland to decrease prolactin secretion which then increases progesterone production because excess prolactin suppresses progesterone. This herb is primarily used to control the symptoms of PMS rather than the symptoms of menopause; however, vitex can be used together with other natural agents during the menopausal period.

Warning: Prolactin is so dangerous in patients with hormone-dependent cancers that the Life Extension Foundation advocates prolactin suppression drug therapy (Dostinex, 0.5 mg twice a week) for breast and prostate cancer patients who have excess prolactin in their blood.

A Natural Estrogen Replacement Approach

When choosing a natural estrogen replacement program, one should be certain that the ingredients are standardized to meet pharmaceutical potency. An investigation conducted in 1998 of natural estrogen products sold in health food stores showed that many companies were not using the standardized plant extracts that had been used in the published studies to treat menopausal symptoms. Telephone calls to these companies confirmed that many extracts are "one-to-one" ratios, meaning that relatively little of the active ingredient was present. It should also be pointed out that this investigation also found that respected brand-name supplement companies were using pharmaceutical-grade standardized extracts in their products to treat menopausal symptoms.

An ideal multi-ingredient phytoestrogen supplement should contain concentrated pharmaceutical extracts. If the active ingredients are not standardized, one cannot expect to obtain consistent biological activity.

Several natural hormone replacement formulas are available. A product called Natural Estrogen has been formulated to provide the hormone-modulating effects that can be obtained from plant sources. The Natural Estrogen formula provides phytoestrogens from soy, estrogenic plants such as licorice extract, and hormone-modulating plant extracts such as black cohosh (Cimicifuga racemosa), Dong Quai (Angelica sinensis), and vitex extract. Additional information about how to safely use natural estrogen supplements will appear later in the protocol.

When Natural Estrogen Is Not Enough
  • Estriol
Some women experience such severe menopausal symptoms that natural, safe forms of estrogen supplements do not provide sufficient relief. If this occurs, and a woman is afraid of the risks of cancer and the side effects of long-term therapy with estrogen drugs approved by the FDA, there is a third option. Estriol is used extensively in Europe for estrogen replacement therapy in menopausal and postmenopausal women. Progressive physicians in the United States have recently begun prescribing estriol for menopausal symptoms. Estriol can be obtained in the United States from compounding pharmacies with a physician's prescription.

Evidence suggests that estriol offers many of the benefits of more traditional estrogen-replacement therapies, but without the harsh side effects or longer-term dangers often encountered by other substances and trademarked products (Head 1998).

Why Is Estriol a Safer Form of Estrogen?

The primary forms of estrogen synthesized by the body include three substances: estrone, estradiol, and estriol. Estrone sulfate is one form of estrogen found in Premarin, while 17-estradiol is the only form of estrogen found in the products Estrace and Estraderm. Estrone and estradiol may significantly increase the risk of breast and ovarian cancer. According to the Merck Manual, conjugated estrogens are substances that have even been listed as known carcinogens. Yet, in the past, these synthetic estrogens were the only estrogens that most traditional medicine physicians prescribed.

Estriol, on the other hand, is a weak estrogen that provides many of the anti-aging benefits of estrogen replacement therapy, apparently without the risk of cancer. Consider this evidence that estriol is benign: during pregnancy, huge amounts of estriol are secreted by the placenta to protect the fetus. Urinary assay of estriol is used to assess the viability of the fetus.

Since estriol is a weak estrogen, larger amounts must be used for ERT. Estriol is used in doses of 2-8 mg daily. A dose of 4-6 mg of estriol can be as effective in some instances as 0.6-1.25 mg of conjugated estrogens such as Premarin. One of the most common side effects of standard estrogen therapy is endometrial hyperplasia, or hyperproliferation of the cells of the uterine lining, a condition that over time can result in uterine cancer. Endometrial hyperplasia, which sometimes occurs at younger ages, will be described in more detail later in the protocol. However, most investigators have found that use of estriol therapy, even at the high dose of 8 mg a day, does not cause endometrial hyperplasia.

Caution: When using any form of estrogen replacement, it is advisable to supplement with a natural progesterone as well, in order to achieve a balanced hormone combination that is similar to the premenopausal period.

Some patients require a combination of estriol and estradiol and/or estrone in order to negate any menopausal side effects. Women who are taking estriol alone and who do not have sufficient relief from hot flashes may obtain relief by adding black cohosh to the regimen. Consider trying this first. The goal is to achieve the natural hormonal balance necessary for the individual female to feel her best, while minimizing any risk of lethal side effects. The best way to ascertain this balance is to evaluate symptoms (how the woman feels) and measure the levels of the metabolites of the hormones in her blood, her tissues (saliva), or in urinary excretion. This dual approach is most effective. Testing methods will be discussed later on in this protocol.

In an early study by scientists at the Medical College of Georgia (Augusta), 52 women with severe menopausal symptoms were given estriol succinate continuously for 6 months in doses of 2-8 mg daily. Significant improvements in symptoms were noted within 1 month of the start of the study and they persisted as long as estriol therapy was continued. The degree of symptom improvement was directly related to the dose. Symptom relief was moderate at 2 mg daily, but was marked at 8 mg daily (Tzingounis et al. 1978).

Estriol therapy 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 flashes 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 was conducted by Lauritzen (1987) at the University of Ulm (Germany). The investigators concluded: "Estriol therapy was successful in 92% of all cases. In 71%, hot flashes 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%." This study also found that forgetfulness, loss of concentration, irritability, and heart palpitations were remarkably improved towards normal. Furthermore, the number of patients experiencing migraine headaches decreased from 33 to 12. Atrophy 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."

As described earlier in the protocol, 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 (Smetnik 1997).

Although no studies have yet been conducted in the United States to determine if estriol therapy can prevent osteoporosis, a prospective double-blind study was conducted at the Chinese Great Wall Hospital (Beijing, China) on 136 postmenopausal women (0.5-21 years since menopause) using nylestriol (CEE3), a long-acting estriol derivative (CEE, conjugated equine estrogen). The physicians found that the placebo group had significantly greater loss of bone mass and higher low-density lipoprotein levels when compared with the treated group. They concluded that this study indicates that "CEE3 is effective and acceptable for preventing bone loss and lipoprotein lipid disorder in postmenopausal women." Long-term CEE3 medication and its effects on the endometrium and the regimen of progestin combination await further study (Cheng et al. 1992).

There is direct evidence from animal studies and indirect evidence from human studies that estriol can prevent breast cancer. Much of this work was 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, only 48% developed tumors (Lemon et al. 1989). In an earlier 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 1980). Because of the anticancer effects of estriol in animals, Lemon had also looked at the question of whether estriol is related in any way to breast cancer in humans. He found that women with breast cancer have low levels of estriol relative to other forms of estrogen (Lemon 1977).

The evidence about estriol as a safe alternative estrogen therapy was well-summarized by the Medical College of Georgia scientists, who concluded: "Estriol deserves a place in our therapeutic resources" (Tzingounis et al. 1978). However, estriol alone in many women is insufficient to relieve the postmenopausal symptoms, and estriol alone may not prevent the development of osteoporosis in susceptible women. In those situations, other estrogens such as estradiol and estrone could be added to the regimen. The approach to treatment will be discussed in more detail later on in this protocol.

The Epidemic Deficiency of Progesterone
  • Preventing Osteoporosis
  • An Anti-Aging
  • Prevent Breast Cancer
  • Potential Dangers
Throughout mature life, women will experience a gradual loss of another critical hormone, progesterone. This decline becomes significant as women get closer to menopause. Symptoms of a progesterone deficit include premenstrual discomfort, night sweats, and hot flashes, along with a loss of the sense of well being (depressed feelings). During and after menopause, natural progesterone synthesis often grinds to a halt, setting the stage for a host of menopausal miseries and degenerative diseases.

In the past, progesterone was given only to women who had an intact uterus (to prevent unopposed estrogen-induced uterine cancer in women who were taking Premarin or other forms of estradiol). Research by Dr. Ray Peat ( http://www.efn.org/~raypeat/sub.html ), Dr. John Lee ( http://store.yahoo.com/johnleemd/trutabos.html ), and others has shown that progesterone has many other beneficial uses, including an improvement in bone density to prevent osteoporosis and to offset other menopausal symptoms.

In addition to making women feel better, progesterone may also help to prevent mental decline that can occur with aging. Progesterone has been shown to increase neuronal energy production and to protect brain cells.

Progesterone and Estrogen Prevent Osteoporosis

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

Like all living cells, osteoblasts and osteoclasts require hormonal guidance to properly function. Osteoblasts depend primarily on progesterone and testosterone, while osteoclasts require estrogen-like hormones, including the active ingredients in soy. In the absence of these hormones, osteoblasts and osteoclasts cease to function properly and rapid deterioration of bone occurs. Osteoporosis can occur when osteoclasts dissolve more bone than osteoblasts are able to replace. Natural progesterone has been shown to stimulate the new bone formation required to prevent and reverse osteoporosis (Heersche et al. 1998).

The effects of osteoporosis can also be the result of vitamin and mineral deficiencies, corticosteroid drug therapy, lifestyle choices such as poor eating habits and lack of exercise, and hormonal imbalances such as overproduction of cortisol and underproduction of testosterone. However, the major influence on age-associated bone deterioration would appear to be a severe deficiency of ovarian-secreted estrogen and progesterone.

Continued . . .

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