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Menopause: A Natural Transition.

This article was originally printed in "The Standard" (Vol. 4, No. 1, 2001).

Introduction

Over 40 million women are currently post-menopausal in the United States. The fact that those numbers will increase to 60 million in the next 10 years and the attitudes about menopause are continuing to move from viewing it as a clinical syndrome to a natural transition have opened the way for more natural and comprehensive management of menopausal symptoms. This review will discuss the physiological and clinical aspects of menopause, with a view to both the inevitable and preventable consequences of the climacteric transition. We will focus on the primary menopausal symptoms (hot flashes, insomnia, etc.), as well as the secondary conditions (osteoporosis, heart disease, etc.) associated with post-menopausal hormone levels. A brief discussion of conventional therapies will be followed by a review of natural alternatives and preventative measures. It will be clear that the treatment of menopausal symptoms can be as natural as the transition itself.

Somewhere between the ages of 45 and 55, most women experience a change in their normal menstrual cycle that results in a complete cessation of the cycle. Those transitional years, often referred to as the perimenopausal or climacteric years, lead to a number of physiological and emotional changes that affect a woman's quality of life. However, while the menopausal transition is experienced by women around world, the unique combination of diet, lifestyle (particularly stress), cultural attitudes, and longevity give it particular prominence in the Western world. The additional fact that menopause is accompanied by increased incidence of bone fractures, heart disease, depression, fatigue, loss in mental acuity, increased sexual difficulties and various cancers has often led to the conclusion that the transition itself must be an unnatural state, or even a diseased state. A correct perception of this natural transition, along with the use of natural dietary and supplemental protocols, may completely alter the quality of life of the growing number of women entering this phase of their lives.

Menopause physiology

The female hormonal cycle is an exquisitely controlled system that includes the hypothalamus, pituitary, adrenal, thyroid and gonadal tissues, involving both positive and negative feedback loops. We will not discuss the intricate nature of the menstrual cycle, only the results of its gradual ceasing here (although surgical menopause, a result of removing the uterus or ovaries, may have similar treatments).

At birth, each woman is endowed with 1-2 million primordial follicles. This pool of follicles decreases to about 300,000 by the time of menarche (puberty). Each menstrual cycle, follicle stimulating hormone recruits several hundred to several thousand follicles. Of these, only one (or sometimes several) matures to the point of ovulation while all the others die by atresia. This process results in approximately 400 or so ovulatory cycles within a woman's lifetime and constitutes what are normally referred to as the premenopausal or reproductive years.

The number of follicles left in the ovary reserve seems to be critical to the regulation of the cycle. At about 38 years of age, when approximately 25,000 follicles re main, the rate at which follicles are recruited increases nearly two-fold, resulting in a rapid decrease in the ovary reserve. Follicle stimulating hormone (FSH) levels in these women increase throughout the cycle, signaling the beginning of a loss in the feedback mechanisms. Many researchers believe that the rise in FSH is related to the decreased ovarian production of molecules called inhibins, which are believed to inhibit pituitary production of FSH. Few women notice any dramatic changes at this time since estradiol (E2) and progesterone levels are affected little by these changes (although fecundity is significantly reduced at this age). By age 51, the median age for the final menstrual period, the ovary reserve is about 1,000. This is typically when the "symptoms" of menopause occur, as it corresponds with a significant drop in estrogen production (usually beginning six months to one year before the final menstrual period). It is significant to note that while a woman may stop menstruating at this time, endogenous cycling and ovulation may still occur for months and even years. This is important to understand because treatment of endogenously cycling "post" menopausal women can differ from truly post-menopausal protocols.

Associated Symptoms and Risks

Menopause would be only a curious endocrinology topic except for the fact that a number of vasomotor symptoms and major medical risk factors are associated with the reduction in estrogen production. Let us briefly review some of the most common vasomotor symptoms: hot flashes, night sweats, insomnia, and genitourinary changes.

Vasomotor

Of all the signals that tell of the arrival of menopause, the hot flash (or flush) is probably the most universal. Of American menopausal women, 75% experience hot flash episodes for an average of four years, although only 15% experience severe episodes. The experience is a sensation of heat, sweating, flushing, chills lasting from 1-5 minutes. For many, anxiety and palpitations are also experienced during these hot flash episodes. A slight increase in core temperature with a dramatic increase in peripheral blood flow results in a rapid rise in skin temperature (0.5[degrees] C). Little is known about the exact physiological causes of hot flashes, although warm room temperatures (or warm compresses) can be used to induce episodes. The exact relationship of estrogen to hot flashes is unclear, because while estrogen replacement therapy can reduce hot flash frequencies, there is not a clear relationship between hot flash episodes and serum estrogen levels (comparing symptomatic and a symptomatic menopausal women). The combination of hot flashes, estrogen-related alterations of circadian rhythms, and increased frequency of depression tends to reduce sleep quality in many women during the climacteric. While it is difficult to assess how much each factor plays in decreasing sleep quality, this is a major factor in reducing the quality of life during the menopausal transition. Often, insomnia is the primary reason for seeking medical attention.

Genitourinary Changes

Decreased estrogen during and after menopause causes physiological changes in the genital tissues. The vaginal area becomes dry and thin and loses tone due to lower estrogen levels as time passes. Decreased lubrication and thinning of the vaginal tissues increases infections, irritations, and the chance for mechanical injury. In creased urinary tract infections and incontinence are also related to a lack of tone in the tissue surrounding the bladder and urethra. These conditions, along with menopausal drops in estrogen, progesterone, and testosterone can lead to a dramatic decrease in libido. Very often, hormone replacement therapies or natural remedies that address vasomotor symptoms will also improve symptoms related to the genitourinary system.

Menopausal Risk Factors

While vasomotor symptoms may be the telltale signs of menopause, they are rarely life-threatening and slowly fade once a women is past the climacteric years. The permanent change in hormone levels has been implicated as a factor in the increased risk of several serious life-threatening diseases, such as osteoporosis, heart disease, and cancers of the breast and endometrium. One complication with data implicating the role that menopause plays in these diseases is the confounding factor that age plays. This is particularly true in the case of cardiovascular diseases, depression, decreases in cognitive ability, and the decline in libido. Because, while it is true that there is an increase of each of these with menopause, men of similar ages have a dramatically increased risk of these or similar diseases, demonstrating that these factors are closely linked with aging. Let us look briefly at these conditions and their relationship to menopause.

Osteoporosis

Of all the conditions mentioned, the link between estrogen depletion and osteoporosis seems to be the closest, although even this has been questioned since the loss in bone density begins well before the drop in estrogen. Osteoporosis is a metabolic bone disease that results in deterioration of the micro-architecture of the bone resulting in lower bone mass and increased risk of fractures. Nearly half of the women over 65 will experience an osteoporosis-related fracture in their lifetime. These fractures (mostly of the spine, hip or forearm) dramatically increase the rate of mortality and need for long-term care. One of the most critical factors in the prevention of osteoporosis is reaching peak bone mass prior to menopause. Most women do not accomplish this for a number of reasons, among them are poor diet and lack of weight-bearing exercises. Several reports have shown that something as simple as the consumption of phosphoric acid in soft drinks reduces bone mineralization in postmenopausal women. [1] The very low phytoestrogen intake in Western diets may also play a role in this as well. We do know that estrogen plays an important role in maintaining bone mass in the female by suppressing remodeling and maintaining a balance between osteoblast and osteoclast activities. As menopause is a low estrogen state, the balance is shifted toward the osteoclast (resorption) and away from osteoblast (bone building) activities. While hormone re placement therapy (HRT) is the conventional treatment for osteoporosis, bone loss resumes when HRT is stopped. For many, there exists a need to find an alternative approach that will become part of their lifestyle regimen for the 20-30 years they will spend after menopause.

Adequate intake of calcium, magnesium, and trace minerals, such as boron, silica, selenium, manganese and molybdenum, is important to proper bone metabolism. The mineral strontium has become a promising mineral in the treatment of osteoporosis. The hormone-like activities of vitamins D and K are also vital components in the maintenance of bone mass. Finding all the necessary components in both dietary and supplemental forms, and in a protocol that maximizes convenience and compliance is the key to ensuring a successful therapy.

Heart Disease

It has been hypothesized that menopause is associated with an increased risk of cardiovascular events, and the increase is caused by decreasing estrogen production. However, whether menopause can be concluded to be an independent risk factor is an area of controversy. The difficulty comes with the slow onset of cardiovascular deterioration and the background effects of aging. The positive correlation is related to the dramatic increase in risk when comparing pre- and postmenopausal women and the reduction of risk associated with HRT. Long-term studies are now being conducted to determine the role estrogen and HRT play in preventing cardiovascular related outcomes like atherosclerosis, heart attacks, stroke, and LDL cholesterol.

Factors to Consider

There are many factors that play a role in age of onset or the severity of the symptoms associated with menopause. Studies have shown that women who experience prevalent symptoms related to premenstrual syndrome (PMS) or whose mother experienced severe vasomotor symptoms upon the climacteric have an increased prevalence of experiencing vasomotor symptoms during their menopause. These results may be due to a consistent pattern of hormone regulation throughout one's life (and even genetically related) or may be a function of increased scrutiny and awareness of these symptoms. Two extraovarian sources of estrogen exist that allow for buffering the dramatic loss at the climacteric. The adipose tissues are capable of producing estrone and this is thought to play a role in reducing some vasomotor symptoms in heavier women. While no direct relationship between body mass index (BMI) and hot flashes (or other symptoms) can be predicted in each case, in many individuals the amount of adipose tissue may relate inversely to menopausal symptoms. The other buffering source is the adrenal gland. The role of the adrenal glands and their ability to modulate stress is often not taken into consideration by doctors when treating patients with climacteric complaints.

If the adrenal gland is incapable of responding adequately to stresses put on it, the symptoms of menopause are likely to be exacerbated. Checking adrenal stress (via cortisol and DHEA-S levels) is a simple addition to many of the salivary tests that can be done to measure estradiol and progesterone. Treating an exhausted adrenal system may dramatically improve symptoms with little other intervention. Other factors to consider are social status, parity, education, smoking, exercise, hysterectomies (with or without ovarectomies), age at menarche, ethnicity, oral contraceptive use, and occupation; all of which can play a role in the onset or severity of menopausal symptoms. [25,26,27]

Hormone Replacement Therapy (HRT)

Conjugated estrogens, which are a mixture of active estrogens derived from the urine of pregnant mares, have been in use in the United States since the early 1940s. The use of estrogens increased for decades following, for conditions like osteoporosis and vasomotor symptoms. In the early 1970s, after evidence strongly linked unopposed estrogen therapy (estrogens without additional progesterone) with increased risk of endometrial cancers, the long-term safety of hormone replacement therapy came into question. Until 1992, Premarin was the only FDA approved oral estrogen product; others have since been approved. Several estrogen and estrogen-progestin products are now used for the treatment of vasomotor complaints and for risk reduction of heart disease and osteoporosis.

The role of estrogens has been broadened by the use of selective estrogen receptor modulators (SERMs). These are agents that produce estrogen-like effects on some tissues (like bone) and antagonize estrogen in others (reproductive tissues). Tamoxifen and raloxifene are the best-studied and most used SERMs for osteoporosis and breast cancer protection. The assumption often made is that every menopausal woman needs some form of HRT and should be on it indefinitely. This assumption is being challenged both for its own inherent risks and the desire of women to choose alternative and more natural routes of menopausal treatments. We have known that unopposed estrogen therapy increases the incidence of endometrial cancer, a risk reduced by the addition of progestins. This year we have learned that the estrogen progestin regimen increases breast cancer risk beyond the risk already associated with estrogen alone. [2] Additionally, long-term HRT is associated with gall bladder disease, liver disease, increased thromboembolic events, and the various cancers already mentioned. With the many natural options available, and increasing positive clinical data, health care professionals should no longer limit their patients' options to conventional HRT. Clearly there are cases where HRT may be the best option for an individual woman, but only when other options have been ruled out. Let us consider some of these other options.

Natural Approaches

It is important to properly assess the needs of patients and their desired outcome. As menopause is viewed and experienced differently by each woman, it is critical to develop a protocol that reflects her desire for improved quality of life and takes into consideration her risk factors for diseases for which no symptoms yet appear.

Diagnosing Perimenopause

Perhaps one of the most important aspects of treating menopause is knowing exactly where in the process the patient is. That is, diagnosing whether the patient is endogenously cycling, ovulating, or fully post-menopausal. What is her progesterone to estradiol ratio? One of the best and simplest ways to answer these questions is with salivary hormone analysis. The use of salivary free-fraction analysis of steroid hormones like estrogens, progesterone, cortisol, and DHEA is not only becoming more common, it is becoming the preferred way of measuring these hormones. [3]

At the early stages of perimenopause, luteal phase deficiencies may lead to reduced progesterone production and irregular bleeding when compared to normal pre-menopausal patterns. Since estrogen production often does not fall until six months before the final menstrual period, this can lead to an estrogen dominant phase within perimenopause (this is also typical in fully post menopausal women). Since it is best to keep the progesterone:estrodiol ratio within a 20:1- 30:1 ratio, knowing both the estradiol and progesterone levels is beneficial to selecting the proper therapy. It is relatively easy to give natural progesterone in sublingual, oral or cream forms to bring this ratio into balance. When the patient is confirmed postmenopausal, a single salivary sample is adequate, whereas a women who is endogenously cycling should have samples taken throughout the cycle (even if she has no menses) to gather the necessary diagnostic data. Additionally, salivary cortisol, DHEA, and testosterone levels help diagnose adrenal or androgen deficiencies that may alter therapies.

Natural Hormone Replacement

After extracting either [beta]-sitosterol from soy or diosgenin from wild yam (Dioscorea villosa), these compounds can be further converted into estradiol, estrone, estriol, progesterone or DHEA. These are identical to the structures made endogenously and can be used therapeutically. A popular practice of many physicians is the compounding of natural estrogens into a tri-estrogen formula (Tri-Est). Most often this consists of a compound that is 80% estriol, 10% estrone and 10% estradiol. A typical formula provides 1 mg estriol, 0.125 mg estrone and 0.125 mg estradiol with 40 mg of micronized oral progesterone. A Bi-Est formula is also used and eliminates the estrone component. Many researchers feel that the balance between these various hormones allows for the most natural kind of hormone replacement therapy. Physicians should talk to a compounding pharmacist for more details on this form of therapy.

Diet and Supplementation

There is certainly a lot to be said about a proper diet through one's lifetime, and several extremely popular diets exist. Suffice it to say that before dealing with any of the complex symptoms that are associated with menopause, it is important to know that each patient's metabolism is able to perform its required functions -- not hindered by a lack of vitamins, minerals, calories, essential fatty acids, etc. A daily regimen including a quality multivitamin and mineral supplement, as well as supplemental oils like flax, evening primrose and fish oils, should be considered as a baseline for additional supplements. Additionally, foods containing phytoestrogens may be able to significantly alter several of the immediate symptoms and risk factors associated with menopause. Positive, but limited research has been conducted with hesperidin (a bioflavonoid) and vitamin C, vitamin B6, evening primrose oil and gamma-oryzanol (a ferulic acid compound isolated from rice bran oil). Gamma-oryzanol at 300mg/day for 8 weeks was able to reduce climacteric complaints 85% (Kupperman Index, which measures 11 different vasomotor symptoms associated with menopause) and significantly reduce total cholesterol, triglycerides and increase HDL cholesterol in cases with hyperlipidemia. [24]

Botanicals

Many herbs and herbal extracts have been used to help alleviate the symptoms associated with the climacteric. We will discuss some of the more common ones here, and briefly mention a few more that you may come into contact with.

Black Cohosh (Cimicifuga Racemosa)

Black Cohosh is a plant native to eastern North America. The root and rhizome portion had been used by Native Americans, who dubbed it "squaw root", long before its introduction to settlers and Western herbalists. The pharmacological and clinical research of the past several decades has made it the most widely used natural alternative to HRT in the Western world. The German Commission E has listed black cohosh as approved for PMS, dysmenorrhea or menopausal (climacteric) neurovegetative (vasomotor, etc.) ailments.

The primary, and presumably, active components found in the roots of black cohosh are a group of triterpene glycosides. Among these are acetin, cimicifugoside and the often-standardized 27-deoxyacteine. Whether these compounds work like classic phytoestrogens is still under some dispute, with conflicting research data. [4,5] Much of the dispute rests in the presence or absense of the isoflavone formononetin; and whether this is a contamination of the extract or a result of differing extraction procedures or even sub-species differences. What we do know is that clinical trials of menopausal symptoms consistently show that extracts of black cohosh are able to reduce or eliminate many of the disturbing vasomotor symptoms. It seems that black cohosh is able to reduce luteinizing hormone (LH) levels in menopausal women, a result many people conclude to be an interaction directly with receptors located within the hypothalamus-pituitary region. [6] LH surges are thought to participate as a main trigger for hot flashes, the main symptom relieved by black cohosh preparations.

In the early 1980s, the effectiveness of a black cohosh extract (standardized liquid) was studied using 629 patients with menopausal complaints. [7] After only four weeks of treatment, a clear improvement was documented by 80% of the women, and after 6-8 weeks 50% reported a complete disappearance of symptoms. While this study lacked a placebo control group, these observations, along with no reported dropouts due to side effects, show the kinds of affects reported by hundreds of doctors in Germany for years prior to this study. A second study compared a tablet containing a standardized extract of black cohosh (80 mg) with 0.625 mg of conjugated estrogens (Premarin) or 2 mg of diazepam, in the reduction of menstrual complaints. Each was able to significantly lower menopausal, as well as mood-related symptoms, but only black cohosh and estrogens were able to increase vaginal epithelium proliferation. The authors conclude, "The herbal treatment allows for the most risk-poor therapy with optimal effectiveness in comparison to hormones and psychopharmaceuticals, demonstrates a remarkable spectrum of action on the menopausal syndrome, has no toxic side effects, is suitable for long-term therapy, and is the medication of choice in cases of mild-to-moderate menopausal ailments." [8]

The results of this open study were later confirmed by a randomized, double-blinded study with placebo and estrogen. [9] The first group was given a preparation of black cohosh extract (4 mg of 27-deoxyacteine) per day. Group 2 received 0.625 mg conjugated estrogens, and Group 3 received placebo. Results were scored using the Kupperman Index, Hamilton Anxiety scale (HAMA), and maturation indices on vaginal epithelial maturation. The results showed that the black cohosh group improved in all categories, when compared to placebo and even in relation to the estrogen group (recall that no progesterone was added). This estrogen-like potential was confirmed when the same dose was just as effective as estriol, conjugated estrogens, and an estrogen-progestin combination in improving postoperative ovarian functional deficits after hysterectomy in young women. [10] While the majority of these articles are published in German journals, a few excellent review articles have been published in English. [11,12,13,14]

Dosing information for black cohosh has been somewhat confusing over the past decade. The original papers seem to have used daily amounts of extract yielding 8 mg of triterpenes (usually measured as 27-deoxyacteine).

Most of the studies then began using half of that amount per day (4 mg) in divided doses. Recently, a manufacturer of one of the extracts suggested only 2 mg per day is needed for the effect noted with the higher amounts. This is likely due to the participation of other, non-triterpene components. A quality extract containing 2-4 mg of triterpenes daily is therefore recommended. Expect at least two weeks and often four weeks before symptomatic changes occur. Recall that black cohosh has primarily been shown to reduce vasomotor and vaginal symptoms; no clear research shows its relation to reducing risk factors associated with cancer, heart disease, or osteoporosis. The safety of these herbal preparations has been confirmed in numerous studies, but this herb should not be confused with Blue Cohosh (Caulophyllum thalictroides), an herb, that if used improperly, has potentially toxic effects for women and their unborn children. [22]

Dong Quai (Angelica Sinensis)

The root of dong quai, also know as Chinese angelica, is a widely used remedy in Asia for a variety of female conditions, and is now becoming more popular in the United States. The roots contain a number of volatile oils and coumarins, many of which have been shown to have biological activity. The coumarin, ligustilide, is often used as a standardizing component, whether this is a more active component or simply a marker is not fully understood.

Traditionally, dong quai is thought to have a balancing or tonic effect on the female hormonal system as well as a beneficial effect on the cardiovascular system. Several reviews in English are available covering the use of dong quai. [15,16] It is most often used in Asian remedies with a number of other ingredients. It is difficult to predict what effect dong quai is intended to have as a single ingredient. One recent report that evaluated dong quai's ability to reduce hot flashes and improve vaginal and endometrial indices failed to show any improvement. [17] The failure of dong quai in this study could have stemmed from a number of issues. Primarily, the diagnostic paradigms between traditional Chinese medicine (TCM) and Western medicine are sufficiently different to make a single preparation of dong quai at these doses difficult to assess the value of these findings. The current body of research lacks sufficient information (pharmacologically and clinically) to fully recommend a menopausal protocol that uses dong quai or its extracts alone. Whether a formula that includes dong quai will be effective for a Western diagnosis (by age, FSH, or estrodiol levels), is yet to be clinically tested.

Chaste Tree (Vitex Agnus Castus)

While the use of extracts derived from the ripened berries of the chaste tree have numerous uses in treating women, most often this herbal remedy is used in pre-menopausal women experiencing irregular menstrual complaints. One of the mechanisms proposed for vitex is an increase in LH secretion, which has a progesterone favoring effect. In the early stages of perimenopause, when cycle irregularities and slow persistant bleeding are associated with an estrogen dominant luteal phase, chaste berry extracts would be an excellent herbal choice.

Licorice Root (Glycyrrhiza Glabra)

The major active component in Licorice root is glycyrrhizin, with minor components such as [beta]-sitosterol, formononetin and coumarin. These compounds have estrogenic and anti-estrogenic capabilities. Glycyrrhizin binds both estrogen and androgen receptors weakly, although it has no affinity for the progesterone receptor. [18] Licorice root extracts support the adrenal gland, [28] one of the likely modes that licorice helps with menopausal symptoms. Of course, high levels of licorice root extract should be cautioned in individuals with high blood pressure.

Trans-Resveratrol

Resveratrol is a naturally occurring compound abundant in grapes and other plant foods, produced by these plants under stress to protect them from environmental or pathogenic attack. The trans configuration is virtually the only naturally occurring isomer, and is nearly identical to the synthetic estrogen diethylstilbesterol. This unique structure has estrogenic, antiestrogenic, antioxidant (free radical scavenging), cardioprotective, and anticancer activities. [19,20,23] The ability to act as a potential estrogenic agent, while at the same time protecting against cardiovascular risk factors, inhibiting various cancers, and increasing antioxidant protection, is a po tent combination, especially for the combined risk factors associated with menopause. Based on the protection gained by trans-resveratrol consumption from wine, dosing recommendations are in the range of 2-4 mg per day. [21] Trans-resveratrol can be extracted from grapes or is also commercially available from rhizome extracts of Polygonum cuspidatum, a plant used in traditional Chinese medicine under the name huzhang (tiger cane). While being relatively new to the nutraceutical world, reports of trans-resveratrol's actions are sure to place it in the forefront of natural substances for the treatment of menopause and its related risk factors.

Other Botanicals

Depending on where one looked, any number of botanicals are recommended for various menopausal complaints. The use of St. John's wort extracts (Hypericum perforatum) for depression and Ginkgo biloba extracts for mental acuity are frequently recommended. Preparations of valerian (Valeriana officinalis) and passion flower (Passiflora incarnata) are often recommended for insomnia. Anti-anxiety and calming herbs such as hops (Humulus lupulus), kava kava (Piper methysticum) and German chamomile (Matricaria recutita) are often prescribed by herbalists for emotional balance when necessary. Of course in TCM and Ayurvedic traditions, many herbal preparations would be used depending on the associated symptomology. Most of these herbs or herbal combinations have not been tested using currently accepted Western clinical research outcomes. It should be understood, however, that in clinical settings, many of these remedies are found to be effective by the physicians who are the most familiar with their use.

The original 12 page periodical "The Standard Menopause" can be obtained by calling 1-715-342-9881 or E-mail: mwompi@voyager.net.

Acknowledgement: I would like to thank Jeremy Johnson for gathering and organizing many of the references used to write this review. His assistance and discussion were invaluable and added tremendously to the content of this article.

Tom Guilliams earned his doctorate from the Medical College of Wisconsin where he focused on biochemistry and molecular immunology. He has been the Director of Science and Quality Assurance for Ortho Molecular Products since 1996. Dr. Guilliams' rare passion for product efficacy and thorough research has earned him wide respect. Dr. Guilliams publishes the quarterly periodical "The Standard", a concise update of important issues concerning natural health ingredients. A frequent guest speaker, Guilliams provides training to a variety of health care disciplines in the use of natural medicines. His lectures have stimulated a wide range of professionals, including allopathic medicine groups, acupuncturists, traditional chiropractors natural health organizations and hospitals.

GENERAL REFERENCES

* Menopause: Biology and Pathobiology. Edited by Rogerio A. Lobo, Jennifer Kelsey and Robert Marcus. Academic Press San Diego, CA, 2000.

* Hudson T. Women's Encyclopedia of Natural Medicine. Keats Publishing Los Angelos, CA, 1999.

* Trickey R Women, Hormones & the Menstrual Cycle -- Herbal and Medical Solutions from Adolescence to Menopause. Allen & Unwin, Australia, 1998.

* The Complete German Commission E Monographs. Blumenthal, American Botanical Council, Austin, TX, 1998.

CITED REFERENCES

(1.) Fernando GR, Martha RM, Evangelina R. "Consumption of soft drinks with phosphoric acid as a risk factor for the development of hypocalcemia in postmenopausal women." J Clin Epidemiol, 1999; 52(10):1007-10.

(2.) Schairer C, et al. "Menopausal estrogen and estrogen progestin replacement therapy and breast cancer risk." JAMA, 2000; 283(4):485-491.

(3.) Voss HF. "Saliva as a fluid for measurment of estriol levels." A JO Stet Gynecol, 1999;180(1 Pt 3):226-31.

(4.) Einer-Jensen N, et al. "Cimicifuga and Melbrosia lack estrogenic effects in mice and rats." Maturitas, 1996; 25(2):149 53.

(5.) Kruse SO, et al. "Fukiic and piscidic acid esters from the rhizome of Cimicifuga racemosa and the in vitro estrogenic activity of fukinolic acid." Planta Med, 1999; 65(8):763-4.

(6.) Duker EM, et al. "Effects of extracts from Cimicifuga race mosa on gonadotropin release in menopausal women and ovariectomized rats." Planta Med, 1991; 57(5):420-4.

(7.) Stolze H. "An alternative to treat menopausal complaints." Gyne, 1982; 3:14-16.

(8.) Warnecke G. "Using phyto-treatment to influence menopause symptoms." Die Medizinische Welt, 1985; 36:871-4.

(9.) Stoll W. "Phytotherapy influences atrophic vaginal epithelium." Therapeuticon, 1987; 1:23-31.

(10.) Lehmann-Willenbrock E, Riedel HH. "Clinical and en docrinologic studies of the treatment of ovarian insufficiency manifestations following hysterectomy with intact adnexa." Zentral l Gynakol, 1988; 110:611-8.

(11.) Lieberman S. "A review of the effectiveness of Cimicifuga racemosa (black cohosh) for the symptoms of menopause." J Womens Health, 1998; 7(5):525-9.

(12.) Liske E. "Therapeutic efficacy and safety of Cimicifuga racemosa for gynecologic disorders." Adv Ther, 1998; 15(1):45-53.

(13.) Foster, S. "Black Cohosh: Cimicifuga racemosa. A Literature Review." Her al Gra, 1999; 45:35-49.

(14.) Gruenwald J. "Standardized black cohosh (Cimicifuga) ex tract clinical monograph." Quarterly Review of Natural Medicine. Summer 1998; 117-125.

(15.) Mei QB, Tao JY, Cui B. "Advances in the pharmacological studies of radix Angelica Sinensis (Oliv) Diels (Chinese Danggui)." Chin Med J, 1991; 104(9):776-81.

(16.) Zhu DP. "Dong Quai." A J Chin Med, 1987; 15(3-4):117-25.

(17.) Hirata JD, et al. "Does dong quai have estrogenic effects in postmenopausal women. A double-blind, placebo-controlled trial." Fertil Steril, 1997; 68(6):981-6.

(18.) Tamaya T, Sato S, Okada H. "Inhibition by plant herb extracts of steroid bindings in uterus, liver, and serum of the rabbit." Acta O stet Gynecol Scand, 1986; 65(8):839-42.

(19.) Basly JP, et al. "Estrogenic/antiestrogenic and scavenging properties of (E)-and (Z)-resveratrol." Life Sci, 2000; 66(9):769-77.

(20.) Debasis B, et al. "Phytoestrogen, resveratrol, and women's health." Research Communications in Pharmacology and Toxicology, 2000; 5(1-2):107-21.

(21.) Calebrese G. "Nonalcoholic compounds of red wine: the phytoestrogen resveratrol and moderate red wine consumption during menopause." Drugs Exp Clin Res, 1999; 25(2-3):111 4.

(22.) Jones K, Lawson BM. "Profound neonatal congestive heart failure caused by maternal consumption of blue cohosh herbal medication." J Pediatr, 1998; 132(3Pt 1):550-2.

(23.) Fremont L. "Biological effects of resveratrol." Life Sci, 2000; 66(8):663-73.

(24.) Ishihara M, et al. "Clinical effect of gamma-oryzanol on climacteric disturbance on serum lipid peroxides [English only for Abstract]." Nippon Sanka Fujinka Gakkai Zasshi, 1982; 34(2):243-51.

(25.) Cramer DW, Xu H. "Predicting age at menopause." Maturitas, 1996; 23(3):319-26.

(26.) Torgerson DJ, et al. "Factors associated with onset of menopause in women aged 45-49." Maturitas, 1994; 19(2):83-92.

(27.) Torgerson DJ, Thomas RE, Reid DM. "Mothers and daughters menopausal ages: Is there a link?' Eur J O stet Gynecol Reprod Biol, 1997; 74(1):63-6.

(28.) Adrenal Stress: Measuring and Treating, Volume 3, No. 1, January/February 2000

FACTORS THAT MAY AFFECT THE ONSET OF MENOPAUSE

Early Onset

* Removal of uterus or ovaries

* Cycle length shorter than 26 days

* Smoking or second-hand smoke (reversible)

* Lower number of full-term pregnancies

* Pelvic irradiation or chemotherapy

* Low socio-economic status

* Single marital status

* African-American or Latin descent

* Malnourishment

* Vegetarian diet

* Mother with early menopause

* History of depression

Delayed Onset

* Cycle length greater than 33 days

* Increased full-term pregnancies (parity)

* Use of oral contraceptives

* Moderate consumption of alcohol

* Increased consumption of phytoestrogens

* Increased Body Fat or BMI
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