|Year : 2012 | Volume
| Issue : 1 | Page : 42-49
Nutritional facts and menopausal symptomatology: The role of nutraceuticals
Sukhwinder Kaur Bajwa1, Sukhminder Jit Singh Bajwa2, Anita Singh1
1 Department of Obstetrics and Gynaecology, Gian Sagar Medical College and Hospital, Ram Nagar, Banur, Punjab, India
2 Department of Anaesthesiology and Intensive Care, Gian Sagar Medical College and Hospital, Ram Nagar, Banur, Punjab, India
|Date of Web Publication||3-Apr-2012|
Sukhwinder Kaur Bajwa
Department of Obstetrics and Gynaecology, Gian Sagar Medical College and Hospital, Ram Nagar, Banur, Punjab
Source of Support: None, Conflict of Interest: None
The onset of menopause is considered to be one of the most important phases in the life span of a female. Associated with this stage is the fear of various ailments due to progressively diminishing functions of the ovaries. Hormone replacement therapy (HRT) has been considered the traditional mainstay for achieving therapeutic relief of various menopausal symptoms. During the last few years, complimentary products and nutraceuticals have gained immense popularity when compared with HRT. The benefits of these prophylactic and therapeutic interventions have yet to be proven with certainty and these regimens are not absolutely free from side effects either. However, the these products have been researched extensively throughout the globe, and many studies are still in pipeline to prove their definite efficacy and benefits over HRT in relieving menopausal symptomatology. This article is an attempt to elaborate the various clinical facts associated with consumption of nutraceuticals during the menopause period.
Keywords: Coronary artery disease, hot flushes, menopause, nutrition, nutraceuticals, osteoporosis
|How to cite this article:|
Bajwa SK, Bajwa SS, Singh A. Nutritional facts and menopausal symptomatology: The role of nutraceuticals. J Med Nutr Nutraceut 2012;1:42-9
|How to cite this URL:|
Bajwa SK, Bajwa SS, Singh A. Nutritional facts and menopausal symptomatology: The role of nutraceuticals. J Med Nutr Nutraceut [serial online] 2012 [cited 2019 Mar 24];1:42-9. Available from: http://www.jmnn.org/text.asp?2012/1/1/42/94633
| Introduction|| |
The onset of the fifth decade is considered to be a big turnaround in the life span of a female, as she starts approaching menopause. For many, this transitory period is studded with unknown fears and ailments of the menopause. The onset of menopausal ailments can be devastating for some females as they can lose their confidence, and self-esteem can get shattered with the fast establishing menopause.
Amenorrhea for a continuous period of 1 year establishes the menopause and results from the cessation of the ovarian functions. The ovarian functions start diminishing in the late thirties and estrogen production stops completely during the mid fifties. Approximately 70 million women in the United States are affected in one way or the other due to estrogen deficiency.  Although the average life span of an Indian female is 65 years when compared with 80 years in the United States, still Indian females have to spend one third of their life span with possible ailments of menopause. These ailments may present in the form of severe hot flushes, sweating, insomnia, osteoarthritis, vaginal dryness, urinary symptoms, and so on. These menopausal and peri-menopausal symptoms can be extremely distressing and painful and demand attention of the attending physician to provide the best treatment with optimal results and minimal side effects. ,
Hormone replacement therapy (HRT) is considered universally the best and most effective intervention for palliation of these symptoms. , However, in developing nations such as India, HRT has not been able to gain the popularity and the momentum it achieved in the western nations. Numerous factors including reluctance by physicians to prescribe HRT remain a big hurdle for its successful administration in the affected population. It has been demonstrated that menopausal women are one of the largest segment using alternative medicines. Approximately 80% of the post-menopausal women between the ages of 45 and 60 years have been reported to use non-prescription and self-medicated therapies such as herbal medicines, vitamins and minerals, homeopathy medicines, acupuncture, and meditation for the alleviation of menopausal symptoms. ,
| Prescribing Trends: Complimentary Therapies Versus HRT|| |
In spite of its proven effectiveness in prevention and alleviation of menopause-related symptoms, treatment with HRT remains a laggard in the developing nations. The guidelines of American Association of Clinical Endocrinologists are important benchmarks while selecting various therapeutic and preventive regimens for relieving the symptomatology of menopause. However, the failure of HRT to gain popularity can be ascribed to a multitude of factors that include but not limited to: ,,,,
- Fear of development of neoplasia especially of breast and uterus
- Onset of breakthrough or cyclic vaginal bleeding
- The higher expense HRT intervention when compared with other remedies
- Unavailability in majority of the rural areas of India
- Reluctance to imbibe a regular medicine-taking habit
- Shortage of specialists having knowledge of administration of HRT
- Shortage of appropriate facilities in the peripheral sector
- Lack of compliance and a regular follow-up
- Need for screening before initiation of HRT such as mammography, lipid profile, pap smear, ECG, and blood sugar leads to many dropouts.
- Considered to be a natural phenomenon by many and therefore do not think any need for initiating HRT.
- Family history of thromboembolism, carcinoma breast. and cardiovascular disease are important risk factors.
- Individual clinical states prohibits its use such as undiagnosed vaginal bleeding, suspected carcinoma breast, previous or current episode of venous thromboembolism, untreated hypertension, active liver disease, and porphyria cutanea tarda.
| Complimentary and Alternate Therapies|| |
Due to the above mentioned reasons and some other sociocultural factors, complementary therapies have gained a wider acceptance especially among the rural female population. As per the data available from a most recent study, approximately 68% patients opted for alternative therapies over HRT for the alleviation of menopausal symptoms. Surprisingly, satisfactory results were obtained in 62% of the studied population.
Phytoestrogens (dietary estrogens)
Phytoestrogens are currently the most popular form of alternative therapy for relief of menopausal symptoms besides HRT.  These agents are known to possess natural protective properties which include but not limited to anti-viral, anti-fungal, anti-bacterial, anti-oxidant, anti-mutagenic, anti-proliferative, anti-inflammatory, and protective estrogenic properties. These agents are derived from the plants, and their chemical structure and efficacy is almost similar to the oestradiol.  More than 300 plants have been identified which are reported to possess agents with similar phytoestrogen-like activity. Broadly speaking, phytoestrogens can be classified into three main categories
The most active and commonly used isoflavones are genistein and daidzein and the common sources for these agents being soybeans, chick peas, red clover, and legumes.  Their actions clinically mimic that of natural estrogens and appear to be selective modulator for the β-estrogenic receptors and exerting almost one third potency when compared with oestradiol. However, they also appear to have weak activity at α-receptor binding with an estimated potency of 0.001 when compared with estradiol. These receptor affinities are responsible to a large extent in predicting the mechanism and degree of action of these plant-derived isoflavones. On oral consumption, these primary isoflavones are broken down by the gut enzymes into active heterocyclic metabolites which are mainly responsible for the estrogenic properties exerted by these compounds. 
Lignanes are primarily found in high fiber diet such as flax seeds.
Coumestans can be derived from various varieties of beans such as split peas, pinto beans, and lima beans. However, alfalfa and clover sprouts are the richest sources of these compounds.
Herbal derivatives (non-phytoestrogens)
Red clover are also isoflavones which have got a possible role in alleviating the symptoms of hot flushes during menopause as has been successfully demonstrated by various placebo controlled trials. The active isoflavone ingredients in red clover plant are biochanin A and formononetin. This natural agent is considered to be safe and recommended doses for consumption vary between 40 and 160 mg daily. Although few concerns have been raised from time to time regarding development of breast cancer on consumption of red clover, but there are no literary data which prove this aspect. 
The active ingredient of black cohosh, remifemin, is prepared from the roots and rhizomes of a North American perennial plant which is also known by the name of Actaea racemosa. It is considered to be helpful in the treatment of menopausal symptoms, primarily vasomotor, and the claims have also been supported by the American College of Obstetricians and gynaecologists. There have been some concerns about the potential hepatotoxic effect of black cohosh, but the recent researchers have found it to be safer during menopause. ,
St. John's wort
The mechanism of action of the active ingredients of this plant includes a SSRI type effect which helps in tiding over the symptoms of depression in majority of the females. A great care has to be exercised while using this agent as it can have adverse drug interactions including warfarin and OCPs. 
It is considered a good natural agent for curing menopause symptoms, but nothing conclusive has come up till now. It has been used widely for the various medicinal and recreational purposes. Neurotoxicity and hepatic toxicity are two major concerns that limit the use of Kava kava for routine treatment of menopausal symptoms. 
Dong quai (female ginseng)
Like many other herbs originating from China, this postmenopausal remedy is an herb native of China. , Also known by the name of "female ginseng," this herb contains phytoestrogens and vitamins A, E, and B12 which are immensely helpful for the treatment of menopausal ailments. The main mechanism of action of this herb is by exerting a vasodilator action on the blood vessels. The increased blood flow resulting from vasodilatation helps in tiding over the hot flushes and vaginal dryness. The sedative action of this herb may be beneficial during stress and mood swings resulting from hormonal changes of menopause and can also lead to some significant side effects such as decreased attention during work and insomnia on discontinuation. , The other benefits of Dong quai include some possible positive effects on the cardiac tissue, and the overall reported decrease in severity of menopausal symptoms is somewhat estimated at 25%.  The daily recommended dosage of dong quai is between 400 and 600 mg and the combination of Dong quai with black cohosh is demonstrated to be of synergistic nature in relieving the symptoms of menopause.
Traditionally, maca root was used in food to increase the aphrodisiac and sexual activity especially in South America and Spain. Additionally, it has also been reported to possess beneficial properties in relieving the menopausal symptoms. Surprisingly, this natural occurring plant does not contain any component related to estrogen but its active ingredient helps in achieving a good hormonal balance in the body. This helps in fighting not only the ailments of menopause such as hot flushes and vaginal dryness but also increases the libido, decreases the incidence of osteoporosis, and prevents the loss of memory. This natural remedy also contains other beneficial component such as magnesium, calcium, zinc, and iron besides various vitamins. The recommended dosage of maca root is estimated at 900 mg which can be consumed three times daily either with meals or tea. 
Even though consumption of ginkgo is widely distributed, but its role in cure of menopausal symptoms remains controversial. However, few studies have reported with certainty that it helps greatly in relief of cognitive symptoms as well as anxiety and depression associated with menopause. 
This plant is considered moderately beneficial for relieving symptoms related to breast and menopause as it produces seeds which are rich in gamma-linolenic acid. However, various studies are at variance with regards to its role in reliving the symptoms of hot flushes. ,
Its utility has not been proved with definite certainty, but its role in relief of premenstrual symptoms is definitely positive when compared with doubtful action in menopausal states. 
Besides these common herbs, there are numerous other herbal products that have been tried from time to time in various parts of the world and with varying results in alleviation of menopausal symptoms.
Vitamins and minerals
The literary evidence regarding the beneficial effect of various vitamins and minerals in relief of peri-menopausal symptoms is drastically limited. From the available information, it can be derived that vitamin E has a definite role in prevention of hot flushes if consumed in amount of 800 IU/day. A recent meta-analytical study has successfully observed the kinetics of dose-response curves and has concluded that the beneficial effect of vitamin E can be obtained in the dosage of 400 IU [Table 1]. ,
|Table 1: Various classes of alternate and complimentary therapy during menopause |
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| Clinical Menopausal Symptomatology and Alternate Therapeutic Strategies|| |
Hot flushes and night sweats are the most common distressing symptoms which compel the suffering women to opt for alleviating therapies.  HRT has been established successfully to be the most effective intervention for the relief of symptoms related to menopause physiology. There is decreased incidence (<0.25) of hot flushes in women consuming soya isoflavone-rich diet especially in Asian females. , Similarly, numerous randomized double-blind placebo controlled trials have successfully proven the efficacy of soya isoflavones in the prevention of hot flushes during peri-menopausal period. While there are hardly any studies to clearly establish the dose of these supplements for the prevention of menopausal symptoms, some authors have demonstrated consumption of 40-80 mg of isoflavones as an adequate dose. , Authors have also pointed out that instead of consuming only the supplements, the consumption of whole food containing these ingredients is a much better option, especially to avoid the side effects related with higher dosages and longer period administration of isoflavones. Additionally, it has been recommended that women with a positive family history of carcinoma breast and uterus should refrain from using these agents as they can flare up the neoplastic changes.
The other significant nutrient that has been studied extensively is black cohosh which has been advocated to have equal efficacy as that of in vivo estrogen. Few randomized placebo controlled clinical trials have proved that this agent has a clinically significant role in prevention of hot flushes when used in doses of 40 mg which is equipotent to 0.6 mg of conjugated estrogen on daily usage.
Generally speaking, females are less prone to heart disease when compared with male counterparts, partially due to protective action of estrogens.  However, the protective cover is somewhat lost with onset of menopause and diminishing of ovarian functions.  The increased risk of heart diseases associated with menopause is well established. Such risks can be possibly reduced to some extent by modification of dietary habits. High fiber and low fat diet, vitamin E, potassium, magnesium, and other anti-oxidant have cardiac protective properties and can be easily obtained with daily dietary intake of whole grains, fruits, vegetables, legumes, and nuts.  Sea food is a rich source of omega-3 fatty acids which have a proven role in cardioprotective mechanism by decreasing cholesterol, exerting anti-inflammatory action, inhibiting the formation of plaque, and altering the viscosity of blood. Supplementation of diet with grand flax meal and walnuts also provides a good amount of omega-3 fatty acids. However, extreme precautions have to be taken during any elective or emergency surgical procedures as there is increased risk of bleeding in patients who are regular consumer of these foods.
One of the most significant aspects about nutrients and nutraceuticals is the source of origin. Preferably, during menopause, such agents should be obtained from natural sources rather than consuming synthetic preparation as the former get assimilated more completely in the body. Some other possible high-risk factors associated with development of cardiac pathologies during menopause include consumption of alcohol, refined sugar, excess caffeine, processed foods, and salts.
The additional advantages of phytoestrogens include reduction of excess body weight and improvement in lipid profile. Cardiac morbidity decreases substantially with regular intake of phytoestrogens such as soy proteins, as there is enough evidence that cholesterol and LDL levels decrease markedly.  Based on numerous clinical trials, it has been successfully established that a daily intake of 45-50 g soy protein is good enough to reduce the risk of coronary artery disease (CAD) by decreasing the concentration of total cholesterol, LDL, and triglycerides.  Additionally, the role of vitamin E as an anti-oxidant has also been overwhelming as it is considered to prevent atherosclerosis by inhibiting oxidation of LDL and cholesterol as well as inhibiting the platelet aggregation, thereby reducing cardiac morbidity. Some studies have gone to the extent of concluding that levels of vitamins are better predictors of CAD and hypertension development.  These cardiac risks can be reduced to a large extent by consuming 400-600 IU of vitamin E daily if we go by the results of these studies. Similarly, role of vitamin B complex cannot be underestimated as adequate levels of vitamins B6, B12, and folic acid convert harmful homocysteine to an inert metabolite cystathionine. The decreased levels of estrogens result in increased levels of homocysteine and reduced conversion of homocysteine to cystathionine, thereby increasing the risk of CAD in menopausal women.
Osteoporosis and decreased bone mineral density is a common feature nowadays among the post-menopausal females.  The resultant pathological states are responsible for various bone degenerative diseases and high propensity for fractures especially femur, hip, and spine. Osteoporosis is one of the most common cause of knee joint stiffness and pain in the post-menopausal females. Although numerous therapeutic interventions, both conservative and surgical, have been tried, nothing can replace maintenance of good dietary habits and a normal BMI for prevention of knee morbidity. Isoflavones have been considered as protective in prevention skeletal morbidity in post-menopausal females.  Animal studies have successfully proved the role of phytoestrogens in reducing the risk of osteoporosis and increasing bone mineral density.  Few studies have successfully established the protective role of genistein, an isoflavone, in post-menopausal osteopenic women for prevention of bone loss at vertebra and femur if consumed to the extent of 54 mg daily. , Similarly, maintenance of bone mineral density and prevention of skeletal morbidity in long bones have been claimed with consumption of 40-80 mg of soy hypocotyls isoflavones. Consumption of 80 mg of soy germ, anotherisoflavone helped in achieving not only prevention of osteoporosis, but also therapeutic efficacy in many post-menopausal women.  In addition, the incidence of bone fracture exhibits inverse relationship with soy protein intake in women over 45 years as evident from the observations of one large study.
The aging process whether in males or females is highly responsible for macular degeneration, but the menopausal females are more prone to this pathological entity leading to loss of vision.  The incidence increases dramatically after the age of 40 at approximately 9% and increases proportionally thereafter during every decade of life. No therapeutic intervention is effective for macular degeneration and preventive measures can ensure the advancement of this disease.  The risk factors can be modified by adopting good dietary habits as the role of vitamin D is considered to be highly protective.  The mechanism of the disease prevention with vitamin D is possibly mediated through immunomodulation and prevention of inflammatory changes.  Not only ophthalmological manifestations can be prevented with adequate vitamin D intake but also numerous other aging-related pathologies leading to chronic diseases can be prevented. Various studies have established the decreased risk of macular degeneration with daily dietary intake of vitamin D to an extent of 400-600 IU.
Psychological and cognitive changes
Mood fluctuations, emotional labile states, depression, and many other psychological changes are associated with onset of menopause. These pathological states do require urgent attention as these changes can deteriorate at a rapid pace. The resulting changes may bring a state of relatively deficient food intake. The nutrient and nutraceuticals have an important role at this stage of life. Chaste bury which is popular as Indian spice is considered to be of immense help in maintaining a normal hormonal milieu. Depressive episodes are common in women during peri-menopausal period, and menopause itself remains an independent predictor of depression. , The treatment of mood swings, insomnia, anxiety, and night sweats during menopausal period with low-dose estrogen and progesterone has been successfully established by various studies. Even isoflavone has been successfully used in treatment of insomnia during menopause as has been established with polysomnographic analysis. ,
The risk of development of breast cancer and its preventive relationship with intake of anti-oxidants has been widely researched and the observations of different studies are at variance. Largely, the results of these studies have been influenced to a great extent by the status of various hormone receptors. However, a strong observation was made with intake of α-carotene, β-carotene, and lycopene in postmenopausal women as these nutrients were found to exert a protective action and showed an inverse relationship with development of breast cancer.  Phytoestrogens are considered to be highly beneficial in the prevention of cancer. At molecular level, these agents exert their actions by inducing cancer cell differentiation, inhibition of tyrosine kinase and DNA topoisomerase activity, angiogenesis inhibition, and to some extent anti-oxidant effect. 
Metabolic changes and BMI
There is increased tendency of fat deposition in the adipose tissues of abdominal viscera during the menopause. , Although numerous studies have given variable results, but a general consensus regarding higher incidence of diabetes mellitus and cardiac diseases exists in these studies during the menopausal period and aging. ,,,, Further, deposition of fat in the abdomen leads to obesity and metabolic changes which aggravate and increases the incidence of dyslipidemia, insulin resistance, and hypertension during menopause. ,,, Higher association between the abdominal fat deposition and metabolic complications most probably results from increased lipolysis which also leads to a higher level of risk markers such as CRP, LDL, and apolipoproteins. , Surprisingly, few studies have claimed that fat deposition in peripheral adipose tissues when compared with abdominal adipose tissue serves as a protective mechanism against development of cardiac diseases and diabetes mellitus type-II in post-menopausal women. In one study comprising 113 menopausal female participants, it was observed that without the use of hormonal replacement therapy, abdominal visceral fat deposition is strongly associated with deranged metabolic profile and increased resistance to insulin. 
Economics, nutraceuticals, and the menopause
Economic analysis has shown a considerably increasing expenditure on nutrients and nutraceuticals in the last decade as people have become more and more health conscious. There is general tendency of adopting preventive measures as the general public is becoming more aware and intellectual and the literary evidence has become extremely rich throughout the globe. Peri-menopausal women are now turning more toward health sector for the treatment of their chronic degenerative disorders and cardiac problems. The desire to retain a better health in the menopausal period has increased the spending habits of the females throughout the globe especially among the intellectual classes. The approach adopted by the health provider is multifaceted which aims at providing maximum benefit to the peri-menopausal women.
| Conclusion|| |
Till recently, HRT was considered the main prophylactic and therapeutic intervention for the relief of menopausal symptoms. In a quest to find suitable alternatives, newer research has brought many natural agents into the limelight which have gained immense popularity over a shorter period. However, many of these compounds are expensive and highly variable with regards to their efficacy in treating menopausal symptoms but definitely lower than that of HRT. Few compounds such as soy products and red clover have successfully provided clinical benefits. These products not only help in relieving post-menopausal symptoms but also provide a prophylactic cover in the prevention of osteoporosis and cardiovascular diseases. Although these compounds are not free from side effects, their overall profile when compared with HRT is favourable. Further research is mandatory before these products can be considered as definite alternatives to HRT.
| References|| |
|1.||Hodgson SF, Watts NB, Bilezikian JP, Clarke BL, Gray TK, Harris DW, et al. AACE Osteoporosis Task Force. American Association of Clinical Endocrinologists medical guidelines for clinical practice for the prevention and treatment of postmenopausal osteoporosis. Endocr Pract 2003;9:544-64. |
|2.||Thompson B, Hart SA, Durno D. Menopausal age and symptomatology in a general practice. J Biosoc Sci 1973;5:71-82. |
|3.||Freeman EW, Sammel MD, Grisso JA, Battistini M, Garcia-Espagna B, Hollander L. Hot flashes in the late reproductive years: Risk factors for African American and Caucasian women. J Womens Health Gend Based Med 2001;10:67-76. |
|4.||Greendale GA, Reboussin BA, Hogan P, Barnabei VM, Shumaker S, Johnson S, et al. Symptom relief and side effects of postmenopausal hormones: Results from the Postmenopausal Estrogen/Progestin Interventions Trial. Obstet Gynecol 1998;92:982-8. |
|5.||Nelson HD. Commonly used types of postmenopausal estrogen for treatment of hot flashes: Scientific review. JAMA 2004;291:1610-20. |
|6.||Kaufert P, Boggs P, Ettinger B, Woods NF, Utian WH. Women and menopause: Beliefs, attitudes and behaviors. The North American Menopause Society 1997 survey. Menopause 1997;5:197-202. |
|7.||Glazier M, Gina MB, Bowman M. A review of the evidence for the use of phytoestrogens as a replacement for traditional estrogen replacement therapy. Arch Intern Med 2001;161:1161-72. |
|8.||Seidl MM, Stewart DE. Alternative treatments for menopausal symptoms. Can Fam Physician 1998;44:1271-6. |
|9.||Geller Stacie E. Studee Laura, Chandra, Gopika. Knowledge, attitudes, and behaviors of healthcare providers for botanical and dietary supplement use for postmenopausal health. Menopause 2005;12:49-55 |
|10.||Zollman C, Vickers A. ABC of complementary medicine. Complementary medicine in conventional practice. Br Med J 1999;319:901-4. |
|11.||Writing Group for the Women's Health Initiative Investigators. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: Principal results From the Women's Health Initiative randomized controlled trial. J Am Med Assoc 2002;288:321-33. |
|12.||Vashisht A, Domoney CL, Cronje W, Studd JW. Prevalence of and satisfaction with complementary therapies and hormone replacement therapy in a specialist menopause clinic. Climacteric 2001;4:250-6. |
|13.||Elkind-Hirsch K. Effect of dietary phytoestrogens on hot flushes: Can soy based proteins substitute for traditional estrogen replacement therapy? Menopause 2001;8:154-6. |
|14.||Knight DC, Eden JA. A review of the clinical effects of phytoestrogens. Obstet Gynecol 1996;87:897-904. |
|15.||Setchell KD, Adlercreutz H. Mammalian ligans and phytoestrogens: Recent studies on their formation, metabolism, and biological role in health and disease. In: Rowland I, editor. Role of the gut flora in toxicity and cancer. London: Academic Press; 1988. p. 315-45. |
|16.||Van de Weijer P, Barentsen R. Isoflavones from red clover (Promensil) significantly reduce menopausal hot flush symptoms compared with placebo. Maturitas 2002;42:187-93. |
|17.||Huntley A, Ernst E. A systematic review of the safety of black cohosh. Menopause 2003;10:58-64. |
|18.||Duker EN, Kpanski L, Jarry H, Wuttke W. Effects of extracts from Cimicifuga racemosaon gonadotropin release in menopausal women and ovariectomized rats. Planta Med 1991;57:420-4. |
|19.||Zhu D. Dong quai. Am J Chin Med 1987;15:117-25. |
|20.||Hardy M. Herbs of special interest to women. J Am Pharm Assoc 2000;40:234-42. |
|21.||Page R, Lawrence JD. Potentiation of warfarin by dong quai. Pharmacotherapy 1999;19:870-6. |
|22.||Elsabagh S, Hartley DE, File SE. Limited cognitive benefits in stage +2 postmenopausal women after six weeks of treatment with Gingko biloba. J Psychopharmacol 2005;19:173-81. |
|23.||Chenoy R, Hussain S, O'Brien PM, Moss MY, Morse PF. Effect of oral gamolenic acid from evening primrose oil on menopausal flushing. Br Med J 1994;308:501-3. |
|24.||Kleijnen J. Evening primrose oil: Currently used in many conditions with little justification. Br Med J 1994;309:824-5. |
|25.||Hammond CB, Nachtigall LE. Is estrogen replacement therapy necessary? J Reprod Med 1985;30Suppl: S797-801. |
|26.||Maclennan A, Lester S, Moore V. Oral estrogen therapy versus placebo for hot flushes. Cochrane Database Syst Rev 2001: CD002978. |
|27.||Lock M. Encounters in aging: Mythologies of menopause in Japan and North America. Berkeley and Los Angeles: University of California Press;1993. |
|28.||Adlercreutz H, Hamalainen E, Gorbach S, Goldin B. Dietary phytoestrogens and menopause in Japan. Lancet 1992;339:1233. |
|29.||Nagata C, Takatsuka N, Kawakami N, Shimizu H. Soy product intake and hot flashes in Japanese women: Results from a community-based prospective study. Am J Epidemiol 2001;153:790-3. |
|30.||Mendelsohn ME. Genomic and nongenomic effects of estrogen in the vasculature. Am J Cardiol 2002;90:3F-6. |
|31.||Grodstein F, Manson JE, Colditz GA, Willett WC, Speizer FE, Stampfer MJ. A prospective, observational study of postmenopausal hormone therapy and primary prevention of cardiovascular disease. Ann Intern Med 2000;133:933-41. |
|32.||Koskinen T, Pyykko K, Kudo R, Jokela H, Punnonen R. Serum selenium, vitamin A, vitamin E and cholesterol concentrations in Finnish and Japanese postmenopausal women. Int J Vitam Nutr Res 1987;57:111-4. |
|33.||Wangen K, Duncan A, Xu X, Kurzer MS. Soy isoflavones improve plasma lipids in normocholesterolemic and mildly hypercholesterolemic postmenopausal women. Am J Clin Nutr 2001;73:235-41. |
|34.||Crouse J, Morgan T, Terry J, Vitolins M, Burge GL. A randomized trial comparing the effect of casein with that of soy protein containing varying amounts of isoflavones on plasma concentrations of lipids and lipoproteins. Arch Intern Med 1999;159:2070-6. |
|35.||Author A. US Department of Health and Human Services. Osteoporosis among estrogen women-United States 1988-1994. Morbid Mortal Wkly Rep 1998;47:969-73. |
|36.||Bassey E, Littlewood J, Rothwell M, Pye DW. Lack of effect of supplementation with essential fatty acids on bone mineral density in healthy pre- and postmenopausal women: Two randomized controlled trials of Efacal v. calcium alone. Br J Nutr 2000;83:629-35. |
|37.||Cecchini MG, Muhlbauer RC, Fleisch H. Ipriflavone inhibits bone resorption in rats: Effects of experimental conditions wAbstr.x. Osteoporosis Int 1996;6Suppl1:317. |
|38.||Clarkson R, Anthony M, Williams J, Honore EK, Cline JM. The potential of soybean phytoestrogens for postmenopausal hormone replacement therapy. Proc Soc ExpBiol Med 1998;217:365-8. |
|39.||Marini H, Minutoli L, Polito F, Bitto A, Altavilla D, Atteritano M, et al. Effects of the phytoestrogen genistein on bone metabolism in osteopenic postmenopausal women: A randomized trial. Ann Intern Med 2007;146:839-47. |
|40.||Chen YM, Ho SC, Lam SS, Ho SS, Woo JL. Beneficial effect of soy isoflavones on bone mineral content was modified by years since menopause, body weight, and calcium intake: A double-blind, randomized, controlled trial. Menopause 2004;11:246-54. |
|41.||Feskanich D, Cho E, Schaumberg DA, Colditz GA, Hankinson SE. Menopausal and reproductive factors and risk of age-related macular degeneration. Arch Ophthalmol 2008;126:519-24. |
|42.||Abramov Y, Borik S, Yahalom C, Fatum M, Avgil G, Brzezinski A, et al. The effect of hormone therapy on the risk for age-related maculopathy in postmenopausal women. Menopause 2004;11:62-8. |
|43.||Snow KK, Cote J, Weining Y, Davis NJ, Seddon JM. Association between reproductive and hormonal factors and age-related maculopathy in postmenopausal women. Am J Ophthalmol 2002;134:842-8. |
|44.||Maartens LW, Knottnerus JA, Pop VJ. Menopausal transition and increased depressive symptomatology: A community based prospective study. Maturitas 2002;42:195-200. |
|45.||Bromberger JT, Schott LL, Kravitz HM, Sowers M, Avis NE, Gold EB, et al. Longitudinal change in reproductive hormones and depressive symptoms across the menopausal transition: Results from the Study of Women's Health Across the Nation (SWAN). Arch Gen Psychiatry 2010;67:598-607. |
|46.||Gambacciani M, Ciaponi M, Cappagli B, Monteleone P, Benussi C, Bevilacqua G. Effects of low-dose, continuous combined hormone replacement therapy on sleep in symptomatic postmenopausal women. Maturitas 2005;50:91-7. |
|47.||Hachul H, Brandao LC, D'Almeida V, Bittencourt LR, Baracat EC, Tufik S. Isoflavones decrease insomnia in postmenopause. Menopause 2011;18:178-84. |
|48.||Cui Y, Shikany JM, Liu S, Shagufta Y, Rohan TE. Selected antioxidants and risk of hormone receptor-defined invasive breast cancers among postmenopausal women in the Women's Health Initiative Observational Study. Am J Clin Nutr 2008;87:1009-18. |
|49.||Kurzer MS, Xu X. Dietary phytoestrogens. Annu Rev Nutr 1997;17:353-81. |
|50.||Lemieux S, Prud'homme D, Nadeau A, Tremblay A, Bouchard C, Després JP. Seven-year changes in body fat and visceral adipose tissue in women. Association with indexes of plasma glucose-insulin homeostasis. Diabetes Care 1996;19:983-91. |
|51.||Ley CJ, Lees B, Stevenson JC. Sex- and menopause-associated changes in body-fat distribution. Am J Clin Nutr 1992;55:950-4. |
|52.||Seidell JC, Oosterlee A, Deurenberg P, Hautvast JG, Ruijs JH. Abdominal fat depots measured with computed tomography: Effects of degree of obesity, sex, and age. Eur J Clin Nutr 1988;42:805-15. |
|53.||Goodpaster BH, Thaete FL, Simoneau JA, Kelley DE. Subcutaneous abdominal fat and thigh muscle composition predict insulin sensitivity independently of visceral fat. Diabetes 1997;46:1579-85. |
|54.||Lovejoy JC, de la Bretonne JA, Klemperer M, Tulley R. Abdominal fat distribution and metabolic risk factors: Effects of race. Metabolism 1996;45:1119-24. |
|55.||Abate N, Garg A, Peshock RM, Stray-Gundersen J, Grundy SM. Relationships of generalized and regional adiposity to insulin sensitivity in men. J Clin Invest 1995;96:88-98. |
|56.||Wajchenberg BL. Subcutaneous and visceral adipose tissue: Their relation to the metabolic syndrome. Endocr Rev 2000;21:697-738. |
|57.||Despres JP. Abdominal obesity as important component of insulin resistance syndrome. Nutrition 1993;9:452-9. |
|58.||Després JP, Nadeau A, Tremblay A, Ferland M, Moorjani S, Lupien PJ, et al. Role of deep abdominal fat in the association between regional adipose tissue distribution and glucose tolerance in obese women. Diabetes 1989;38:304-9. |
|59.||Rendell M, Hulthén UL, Törnquist C, Groop L, Mattiasson I. Relationship between abdominal fat compartments and glucose and lipid metabolism in early postmenopausal women. J Clin Endocrinol Metab 2001;86:744-9. |
|60.||Couillard C, Ruel G, Archer WR, Pomerleau S, Bergeron J, Couture P, et al. Circulating levels of oxidative stress markers and endothelial adhesion molecules in men with abdominal obesity. J Clin Endocrinol Metab 2005;90:6454-9. |
|61.||Piché ME, Lemieux S, Weisnagel SJ, Corneau L, Nadeau A, Bergeron J. Relation of high-sensitivity C-reactive protein, interleukin-6, tumor necrosis factor-alpha, and fibrinogen to abdominal adipose tissue, blood pressure, and cholesterol and triglyceride levels in healthy postmenopausal women. Am J Cardiol 2005;96:92-7. |
|62.||Piché ME, Lapointe A, Weisnagel SJ, Corneau L, Nadeau A, Bergeron J, et al. Regional body fat distribution and metabolic profile in postmenopausal women. Metabolism 2008;57:1101-7. |