Should Women Be Given HRT - Research Proposal Example

Should women be given hormone replacement therapy? Introduction It has been estimated that almost 47 million women would undergo menopause by the year 2030(Hill, 1996). Natural menopause generally occurs between the ages of 45 and 54. When a woman enters menopause both the ovaries begin to shrink and levels of estrogen and progesterone fluctuate as the ovaries strive to maintain the hormone production. This manifests in a variety of bothersome symptoms such as hot flushes night sweat, sleep disturbances, insomnia, vaginal dryness and anxiety which may vary in severity from woman to woman (pht_facts.pdf, 2009). Combined estrogen and progesterone Hormone Replacement Therapy (cHRT) made an imposing entrance in 1970s , although estrogen therapy was already approved in 1942( Moore,2002 ).Eventually it was acknowledged as the only treatment for the distressing symptoms of menopause .WHI- Women Health Initiative (Cauley et.al.,2003) , the first controlled study of HRT in healthy post menopausal women was planned from 1997 to 2005 but was terminated midway when independent data and safety monitoring board elucidated that the evidences of health risks overshadowed its benefits. The data revealed an augmented risk of breast cancer, coronary heart disease, stroke and venous thromboembolism. The post menopausal Estrogen Progestin Intervention (PEPI) Trial (Writing Group ,1996) demonstrated recuperation in bone density in spine and hip bones and concluded that HRT especially estrogen, was constructive for the prevention of osteoporosis and also diminished the damaging Low density Lipoprotein (LDL). Heart and Estrogen-Progestin Replacement Study (HERS) and Women’s Estrogen for Stroke Trial (WEST) exhibited that cHRT and unopposed estrogen replacement therapy were ineffective for secondary prevention of cerebrospinal events in post menopausal women (Hulley, 1998; Viscoli, 2001). These studies have modified our perception towards HRT. The data appears intimidating and has added a lot of mystification to it. Such intriguing results have provoked several questions regarding its use, benefits and risks. The medical fraternity is desperately seeking answer to whether HRT is a boon or a bane? What is the ratio of benefit versus risk? Do the risks really prevail over benefits? HRT is reported to increase bone mineral density (BMD) and trim down the risks of fracture but, aggravates the risk of stroke. Is it good news or bad? Which is more important fracture or a stroke? We do not know how reliable is the data? For instance, the WHI report affirms that ‘estrogen therapy caused fewer cases of breast cancer but the data was not statistically significant’? How can that be possible? How do we interpret such deceptive data? There are several such important findings in the WHI trial which are insignificant, meaning that either they are probably true – or probably not. Such incomprehensible findings need further confirmation. So should we believe that HRT has serious safety concerns or simply ignore them and relax? There is so much of controversy surrounding this topic. Therefore, the objective of this manuscript was is to present each side of the issue by analyzing various relevant research articles. Context Menopause is a normal process of ageing. It is not a disease that needs treatment. Approximately 75 – 80 percent women who enter menopause experience menopausal symptoms. Almost half of them find it distressing while 20-30 percent experience severe symptoms (Palacios, 2003).In the light of its distressing symptoms, the widespread acceptance of HRT by menopausal women is easy to understand. Relief from bothersome symptoms; particularly hot flashes, sleep disturbances, and urogenital atrophy was a great comfort for many women (Rymer et.al.2003). The additional benefit of HRT on improvement and prevention of osteoporosis, a menopause related disease was welcome. In the year 2000 , 46 million prescriptions were written for Premarin (conjugated equine estrogen ) rendering it the second most prescribed drug in US (Fletcher,Colditz ,2002 ).However, since the publication of WHI and HERS (Hulley, 1998; Viscoli ,2001) study reports on menopausal women , the adverse events reported therein have placed a big exclamation mark on its popularity. The ambiguity of safety and complexity of issue have made it difficult for women to take decision about its use. They are in a dilemma of choosing between the distressing menopausal symptoms or hazardous outcomes of HRT such as coronary heart disease (CHD), stroke, cancer etc. Therefore, in order to elucidate the overcast issue, the present article presents a review of some of the most relevant literature on this issue. Different Positions The WHI trial (Cauley et.al. 2003) was one of the largest randomized ,placebo controlled study conducted on menopausal women 50 to79 years of age with intact uterus. The objective behind the study was to investigate whether relative risk reduction of estrogen plus progestin on fracture differs according to risk factors for fracture. The volunteers were randomized to receive a cHRT of conjugated equine estrogen (CEE) 0.625 mg/d plus medroxyprogesterone acetate (MPA) 2.5 mg/day in the form of tablets or placebo. The participants were monitored for 5.2 years for confirmed osteoporotic fracture, bone mineral density (BMD) and global index developed to ascertain risks and benefits were measured at baseline, 1 year and 3 years. The results revealed that the cHRT group had 8.6% fractures as compared to 11% in placebo group with a fracture hazard ratio of 0.75. The effect was the similar in all the women and did not differ by age, body mass index, smoking status, history of falls, personal and family history of fracture, total calcium intake, past use of hormone therapy, BMD etc. After 3 years of treatment total BMD improved by 3.7 % in cHRT as compared to 0.14% in placebo group. The risk hazard for global index was similar across the subgroups of fracture risk scale (low, medium and high). The study clearly indicated that cHRT increased BMD and reduces the risk of fracture in menopausal women. The decreased risk of fracture was attributed to cHRT and was observed in all risk subgroups. The hip and clinical vertebra fractures were significantly reduced by 34% and total osteoporotic fracture by 24% which showed that cHRT is beneficial as far as osteoporosis is concerned. However, when considering the effect of HRT on other important diseases, risk overweighed benefits even in women considered at high risk of fracture. All stastical analysis used time to event methods and the endpoints have been presented as hazard ratio. The data of the study was statically significant and no ambiguous terms were used. The WHI (Cauley et.al., 2003) randomized controlled trial consisted of two treatment cohorts, a group of posthysterectomy women treated with CEE alone and another group of women with intact uterus received the combined therapy of CEE plus MPA .The CEE plus MPA group was terminated after 5.6 years due to incidences of cancer and unfavorable global index, coronary heart disease, stroke, pulmonary embolism and breast cancer. As a result the focus of interest began to shift towards assessing the benefits of short term hormone therapy among recently menopausal women. After the termination of the other wing of WHI trial receiving CEE therapy, this interest intensified. Therefore, Prentice et al (2009) carried out further analysis of WHI data with the objective to assess risk versus benefit equation in women who initiated hormone therapy immediately after menopause. It was observed that both the treatment groups exhibited comparatively higher hazard ratio. The group that received CEE alone exhibited elevated thromboembolism, stroke and reduction in hip fracture. The group that received CEE pus MPA exhibited similar results for venous thromboembolism, stroke and hip fractures and also included evidences of longer term elevation in breast cancer, total cancer and global index. These data does not defend the initiation of hormone therapy soon after menopause and presents an unflattering benefit versus risk equation. WISDOM -Women’s international study of long duration estrogen after menopause (Vickers et al, 2007) was a multi centered randomized placebo controlled double blind trial of HRT in postmenopausal women. The objective behind the study was to assess the long term risks and benefits of HRT i.e., cHRT versus placebo and estrogen alone versus cHRT. Post menopausal women aged 50-69 years were enrolled at three different centers UK, Australia and New Zealand. The interventions were conjugated equine estrogen 0.625 mg orally daily (CEE) plus MPA 2.5/5.0 mg orally daily. The primary endpoints intended to be measured were major cardiovascular disease, osteoprotic fracture and breast cancer. The secondary outcomes were other cancers, death from all causes, venous thromboembolism, cerebrovascular disease, dementia and quality of life. The trial was supposed to be followed up for a decade but had to be interrupted prematurely at 11.9 months after the early negative results of Women’s Heath Initiative (WHI) study. The short term data revealed that comparison of cHRT with placebo did not exhibit significant increase in number of major cardiovascular events and venous thromboembolisms. It appeared that the number of breast or other cancers, cerebrovascular events, fractures and overall deaths were the same in placebo and cHRT group implying that cHRT had no role in preventing these secondary outcomes. The comparison of CEE alone versus CEE plus MPA showed that both therapies increased cardiovascular and thromboembolism risks when started many years after menopause. These findings are consistent with the WHI study. However, as the study was discontinued prematurely and there is no data to shed light on the long term risks or benefits of initiating HRT near menopause, which could be different. The WISDOM was terminated before large number of recently menopausal women could be recruited therefore; the ‘critical window’ hypothesis could not be examined to check if estrogen had cardio protective and neuro-protective effects as risk versus benefit ratio for a young menopausal woman may be different from older women. Further research needs to be carried out to assess the risks and benefits of starting HRT near menopause. There were no ambiguous words or phrases or any fallacies in the article. The statistics of the study are significant. Several observational studies had reported that hormone replacement lowered the risk of coronary heart disease in postmenopausal women. In order to determine if cHRT altered the risk for CHD events in post menopausal women with established coronary disease Hulley et al (1998 ) initiated a randomized , blinded , controlled secondary prevention trial on women with CHD and a mean age of 66.7 years. A combined dose of 0.625mg of CEE and 2.5 mg of MPA was administered daily to the treatment group and the controlled group received an identical placebo. The study was followed up for 4.1 years. The primary outcome was the occurrence of fatal myocardial infarction or CHD death. Secondary cardiovascular end points included coronary revascularization, unstable angina, congestive heart failure, resuscitated cardiac arrest, stroke and peripheral arterial disease and all cause mortality. The treatment group and the control group exhibited no difference as far as the primary or the secondary cardiovascular outcomes are concerned. Despite a net increase of 10% High density lipoprotein (HDL) and 11% decrease in Low density Lipoprotein (LDL) in the treatment group as compared to the control group there was a lack of overall effect. The treatment group exhibited a statically significant time trend with more CHD events in one year and fewer in fourth and fifth year. More number of women in study group experienced venous thromboembolism and gall bladder disease. There was no significant difference in fracture, cancer and total mortality. The results show that cHRT was ineffective for women with preexisting CHD. Jankowski et al (2006) conducted a double blind controlled trial on older men and women with the objective of verifying whether dehydroepiandrosterone (DHEA) replacement improved bone mineral density (BMD) and fat free mass . DHEA and its sulfate (DHEAS) are precursors of androgen and estrogen. It is believed that with aging, the levels of DHEA decline resulting in sex hormone dependent physiological changes. Both men and women with low serum levels and age range 60-88 years were enrolled for the study. The treatment cohort received DHEA 50 mg daily whereas the control group was given placebo. Bone mass density (BMD), fat mass and fat free mass were measured before and after intervention. The treated group exhibited statistically significant increase in BMD at hip, trochanter and shaft. Increased lumber spine BMD was observed in females only, indicating sex specificity. The effect of DHEA replacement on fat or fat free mass was not significant. Over a period of one year DHEA replacement therapy improved hip BMD in older adults and spine BMD older women. Sex specific response of DHEA suggests that it could be more effective in women. Although the increase in BMD was lesser than those in HRT studies, still the possibility that DHEA had anti fracture effects cannot be ruled out. As the study was a precursor replacement study and not direct hormone replacement therefore, the results may or may not be extrapolated to HRT. Moreover, the trial produced clinical data in older men and women the results of which may not be pertinent to post menopause women. A trial of longer duration and larger number of patients would be needed to ascertain if it really moderates risk factor. When we compare the results of observational studies and the WHI trial on CHD we come across several discrepancies. The observational studies on post menopausal hormone replacement therapy report a lower risk of CHD whereas the WHI trial reported a higher risk. This disparity may be attributed to limitations of observational study such as the inability to capture clinical events occurring just after initiation of study, major differences in the age of enrollment and hormone therapy initiation in observational and WHI study. Therefore, an observational study was designed by Grodstein et al (2006) to examine the relation of hormone treatment to CHD with respect to time since menopause and the age at hormone replacement on post menopausal women. The follow up time was four years and information on hormone use was ascertained in biennial mailed questionnaire. A proportional hazard model was used to calculate multivariable adjusted relative risks and 95% confidence interval and a sensitivity analysis was also conducted. The results exhibited that the women who began hormone therapy near menopause had significantly reduced risk of CHD. However, there was no relation between hormone treatment and CHD among women who started hormone therapy ten years after menopause, though there was a suggestion of reduced risk. In the sensitivity analysis the authors found that incomplete capture of coronary events occurring shortly after initiation of hormone therapy could not explain the observation of reduced risk for the use of hormone therapy. The authors conclude that there is a possibility that coronary heart disease could be influenced by the time of hormone initiation since menopause and the age at hormone initiation. Analysis of the Points of View on the Issue (ARQ) Cauley, J.A., Robbins, J., Chen, Z., et al (2003). Womens Health Initiative Investigators. Effects of estrogen plus progestin on risk of fracture and bone mineral density: the Womens Health Initiative randomized trial. JAMA, (13), 1729-38. 1. What are the issues and the conclusions? The objective behind the study was to test whether relative risk reduction of estrogen plus progestin on fracture differs according to risk factors for fracture. The study clearly indicates that cHRT increases BMD and reduces the risk of fracture in menopausal women. 2. What are the reasons? The decreased risk of fracture was attributed to cHRT. 2. Which words or phrases are ambiguous? None. 3. Are there any fallacies? No there are no fallacies. 4. How good is the evidence? The hip and clinical vertebra fractures were significantly reduced by 34% and total osteoporotic fracture by 24% which showed that cHRT is beneficial as far as osteoporosis is concerned. This gives fairly good evidence towards the beneficial effects of hormone replacement on osteoporosis. 5. Are there rival causes? None. 6. Are the statistics deceptive? The data of the study was statically significant. 7. What significant information is omitted? The study has been conducted on older women and there is no data to show the effect of hormone therapy on women who began hormone therapy near menopause. 8. What reasonable conclusion is possible? The study clearly indicates that cHRT increases BMD and reduces the risk of fracture in menopausal women. However, the overall risk – benefit profile of cHRT when considering its effects on other important diseases showed that risk overweighed benefits even in women considered at high risk of fracture. Prentice,R.I., Manson,J.E., et al.Robert ( 2009) Benefits and risks of postmenopausal hormone therapy when it is initiated soon after menopause Am J Epidemiol. 170, 12–23 1. What are the issues and the conclusions? The WHI (Cauley et.al.,2003) controlled trial consisted of two treatment cohorts, CEE alone and CEE plus MPA Both the groups were terminated midway’s due to incidences of cancer and unfavorable global index, coronary heart disease, stroke, pulmonary embolism and breast cancer. As a result the focus of interest began to shift towards assessing the benefits of short term hormone therapy in among recently menopausal women. Therefore, Prentice et al (2009) carried out further analysis of WHI data with the objective to assess risk versus benefit equation in women who initiated hormone therapy immediately after menopause. It was observed that both the treatment groups exhibited comparatively higher hazard ratio. The group that received CEE alone exhibited elevated thromboembolism, stroke and reduction in hip fracture. The group that received combined therapy had similar results for venous thromboembolism, stroke and hip fractures but also included evidences of longer term elevation in breast cancer, total cancer and global index. 2. What are the reasons? The unfavorable benefit to risk equation is attributed to cHRT. 3. Which words or phrases are ambiguous? None. 4. Are there any fallacies? None. 5. How good is the evidence? Good enough. 6. Are there rival causes? None. 7. Are the statistics deceptive? The data of the study was statically significant 8. What significant information is omitted? None 9. What reasonable conclusion is possible? The adverse benefit to risk ratio in CEE plus MPA trial of WHI was also applicable to recently menopausal women. Similar to WHI trial, the CEE benefits and risks were almost equal\. According to WHI data there wass no relation between the timing of hormone initiation and development of coronary heart disease. Vickers, M.R., MacLennan, A.H., Lawton, B., et al (2007). Main morbidities recorded in the womens international study of long duration estrogen after menopause (WISDOM): a randomized controlled trial of hormone replacement therapy in postmenopausal women. BMJ, 335(7613), 239. 1. What are the issues and the conclusions? WISDOM -Women’s international study of long duration estrogen after menopause (Vickers et al, 2007) was a multi centered randomized placebo controlled double blind trial of HRT in postmenopausal women. The objective behind the study was to assess the long term risks and benefits of HRT i.e., cHRT versus placebo and estrogen alone versus HRT. The comparison of CEE alone versus CEE plus MPA showed that both therapies increased cardiovascular and thromboembolism risks when started many years after menopause. These findings are consistent with the WHI study 2. What are the reasons? The increased cardiovascular and thromboembolism risks are attributed to hormone treatment. 3. Which words or phrases are ambiguous? None 4. Are there any fallacies? None 5. How good is the evidence? Are there rival causes? None 6. Are the statistics deceptive? The data of the study was statically significant 7. What significant information is omitted? The WISDOM trial was terminated before large number of recently menopausal women could be recruited therefore; the ‘critical window’ hypothesis could not be examined to check if estrogen had cardio protective and neuro-protective effects as risk versus benefit ratio for a young menopausal woman may be different from older women. 8. What reasonable conclusion is possible? Hormone replacement increases the risk of cardiovascular and thromboembolic events when initiated many years after menopause. More trials are required to ascertain the long term implications of hormone therapy near menopause. Hulley,S.,Grady,D.,Bush,T.,Furberg,C.,Herrington,D.,Riggs,B.,Vittinghoff,E., (1998).Randomized Trial of Estrogen Plus Progestin for Secondary Prevention of Coronary Heart Disease in Postmenopausal Women. JAMA. 280(7), 605-613. 1. What are the issues and the conclusions? Several observational studies had reported that hormone replacement lowered the risk of coronary heart disease in postmenopausal women. In order to determine if cHRT altered the risk for CHD events in post menopausal women with established coronary disease Hulley et al (1998 ) initiated a randomized , blinded , controlled secondary prevention trial on women with CHD. The treatment group and the control group showed no difference and there was a lack of overall effect. The treatment group exhibited a statically significant time trend with more CHD events in one year and fewer in fourth and fifth year. More number of women in the treatment group experienced venous thromboembolism and gall bladder disease 2. What are the reasons? These effects can be attributed to hormone therapy. 3. Which words or phrases are ambiguous? There were ambiguous words or phrases. 4. Are there any fallacies? There were no fallacies. 5. How good is the evidence? Good enough. 6. Are there rival causes? None 7. Are the statistics deceptive? No. 8. What significant information is omitted? None. 9. What reasonable conclusion is possible? The results show that cHRT was ineffective for women with preexisting CHD. Jankowski,C.M.,Gozansky,W.S.,Schwartz,R.S.,et.al.(2006).Effects of dehydroepiandrosterone replacement therapy on bone mineral density in older adults: a randomized, controlled trial. J Clin Endocrinol Metab., 91(8), 2986-93. 1. What are the issues and the conclusions? Jankowski et al (2006) conducted a double blind controlled trial on older men and women with the objective of verifying whether dehydroepiandrosterone (DHEA) replacement improved bone mineral density (BMD) and fat free mass . DHEA and its sulfate (DHEAS) are precursors of androgen and estrogen. It is believed that with aging, the levels of DHEA decline resulting in sex hormone dependent physiological changes. Over a period of one year DHEA replacement therapy improved hip BMD in older adults and spine BMD older women 2. What are the reasons? The effect can be attributed to DHEA repacement as DHEA and its sulfate (DHEAS) are precursors of androgen and estrogen. It is believed that with aging, the levels of DHEA decline resulting in sex hormone dependent physiological changes 3. Which words or phrases are ambiguous? None 4. Are there any fallacies? None 5. How good is the evidence? The evidence was good enough. The treated group exhibited statically significant increase in BMD at hip, trochanter and shaft. Increased lumber spine BMD was observed in females only indicating sex specificity 6. Are there rival causes? None 7. Are the statistics deceptive? No What significant information is omitted? None. 9. What reasonable conclusion is possible? Over a period of one year DHEA replacement therapy improved hip BMD in older adults and spine BMD older women. Sex specific response of DHEA suggests that it could be more effective in women. Grodstein,F., Manson,J.E. and Stampfer, M.J. ( 2006)hormone therapy and coronary heart disease: the role of time since menopause and age at hormone initiation. Journal of Women’s Health. 15(1), 35-44. 1. What are the issues and the conclusions? When we compare the results of observational studies and the WHI trial on CHD we come across several discrepancies. The observational studies on post menopausal hormone replacement therapy report a lower risk of CHD where as the WHI trial reported a higher risk. These may be attributed to limitation of observational study such as the inability to capture clinical events occurring just after initiation of study and there were major differences in the age of enrollment and hormone therapy initiation in observational and WHI study. Therefore an observational study was designed by Grodstein et al (2006) to examine the relation of hormone treatment to CHD with respect to time since menopause and the age at hormone replacement on post menopausal women. The results exhibited that the women who began hormone therapy near menopause had significantly reduced risk of CHD. There was no relation between hormone treatment and CHD among women who started hormone therapy ten years after menopause. 2. What are the reasons? The observation of reduced risk for current use of hormone therapy could not be explained by authors. 3. Which words or phrases are ambiguous? None. 4. Are there any fallacies? None. 5. How good is the evidence? There is just a possibility that coronary heart disease is influenced by the time of hormone initiation since menopause and the age at hormone initiation. 6. Are there rival causes? None 7. Are the statistics deceptive? No. 8. What significant information is omitted? None. 9. What reasonable conclusion is possible? The authors conclude that there is a possibility that coronary heart disease is influenced by the time of hormone initiation since menopause and the age at hormone initiation. ` Final Reasoned Point of View HRT and Osteoporosis Bone loss increases during the first 3-4 years of menopause. A third of women over the age of 50 are prone to fracture due to osteoporosis. The literature reviewed in this article shows that hormone replacement therapy reduces bone loss at clinically relevant sites. The WHI trial (Cauley et.al. 2003) exhibited that hormone replacement replaces hip fractures and improved bone mineral density in postmenopausal women. Prentice et al (2009) who further analyzed WHI report on the risks and benefits early initiation of hormone therapy also reported a significant reduction in hip fracture in CEE and CEE plus MPA treated cohorts. Jankowski et al (2006) found that DHEA replacement over a period of one year improved BMD in older adults and spine BMD in older women. Hulley et al. (1998) found only a slight decrease in the rate of fracture in treated group as compared to control which was not significant probably the power was limited. On the contrary, Vickers et al, (2007) reported that hormone therapy had no significant effect on fractures. The literature supports the beneficial role of hormone replacement therapy for osteoporosis. HRT and Cardiovascular disease (CHD) The two cohorts of WHI trial (Cauley et al., 2003) were terminated prematurely due to stroke in conjugation with likelihood of CHD. The WISDOM trial (Vickers et al, 2007) reported significant increase in number of major cardiovascular events in a short span of 11.9 months of follow up after which the trial was prematurely terminated. Hulley et al. (1998) observed that hormone therapy was ineffective in curing post menopausal women with existing CHD, and reported that treated group exhibited a statically significant time trend with more CHD events in one year and smaller number in fourth and fifth year. On the contrary, the observational study (Grodstein et al, 2006) exhibited that the women who began hormone therapy near menopause had significantly reduced risk of CHD but not among women who started hormone therapy ten years after menopause. It appears that HRT really has grave CHD concerns. Other compications The WHI tria (Cauley et.al. 2003) was terminated after 5.6 years due to incidences of cancer and unfavorable global index, coronary heart disease, stroke, pulmonary embolism and breast cancer. Prentice et al (2009) reported that the cHRT treatment group developed venous thromboembolism, stroke and hip fractures in addition to evidences of longer term elevation in breast cancer, total cancer and global index. The short term data of WISDOM trial (Vickers et al, 2007) report HRT did not prevent venous thromboembolisms , breast or other cancers, cerebrovascular events, fractures and overall deaths .According to Hulley et al (1998 ) more number of women in study group experienced venous thromboembolism and gall bladder disease. HRT was ineffective in the prevention of secondary cardiovascular end points including coronary revascularization, unstable angina, congestive heart failure, resuscitated cardiac arrest, stroke and peripheral arterial disease and all cause mortality. This is sufficient evidence to question the safety of HRT. Conclusion Menopause is a normal process of ageing; it is not a disease that could be treated. Women have the right to decide upon the use of hormone replacement therapy. HRT was widely and readily accepted as it relieved the bothersome menopausal symptoms to a great extent. In addition there is sufficient evidence that it prevents and cures osteoporosis – a menopause associated disease. Thus hormone replacement had dual advantages and appeared to be the most promising treatment for menopausal symptoms. However, the other side of the issue is not so pleasant. Be it WHI trial, WISDOM or any other study for hormone treatment, the benefits seem to be overshadowed by the risks. There is no evidence of the benefit of hormone replacement on the prevention or cure of coronary heart disease. However, there are enough evidence to support its role in adverse events such as cancer, stroke, cerebrovascular complications and thromboembolism associated with HRT. It would not be advisable to cure osteoporosis at the cost of inviting dreadful life threatening diseases when other therapies are available for its treatment and prevention. It would be wise to suffer from menopausal symptoms rather than plunging into the death traps of dreadful diseases. Hormone replacement lacks the safety profile needed for an extensively prescribed drug, and therefore should not be recommended to menopausal women. References 1. Hill, K. (1996) the demography of menopause. Maturitas .23,113-27. 2. National Institutes of Health. (2002). Menopausal Hormone Therapy. U.S. Department of Health and Human Sciences. Retrieved on November 14th, 2009 http://www.nhlbi.nih.gov/health/women/pht_facts.pdf 3. Moore, A. (2003). Hormone Replacement Therapy: Dilemmas in 2002 .Trans. Am. Clin. Climatol. Ass, 114, 233-240. 4. Cauley, J.A., Robbins, J., Chen, Z., et al (2003). Womens Health Initiative Investigators. Effects of estrogen plus progestin on risk of fracture and bone mineral density: the Womens Health Initiative randomized trial. JAMA, (13), 1729-38. 5. Writing Group for the PEPI trial. (1996) . Effects of hormone therapy on bone mineral density. JAMA, 276, 1389-1396. 6. Hulley S, Grady D, Bush T, et al.( 1998) Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. Heart and Estrogen/progestin Replacement Study (HERS) Research Group. JAMA, 280,605–13. 7. Viscoli. C.M., Brass, L.M., Kernan, W.N., Sarrel, P.M., Suissa, S. Horwitz, R.I. (2001) A clinical trial of estrogen-replacement therapy after ischemic stroke. N Engl J Med. 345, 1243–9. 8. Palacios S, Calaf J, Cano A, Parrilla JJ. (2003) Spanish Menopause Society (AEEM). Relevant results of the WHI study for the management of the menopause in Spain. Maturitas. 44,83-86. 9. Rymer,J., Wilson,R and Ballard, K. (2003) Making decisions about hormone therapy. BMJ . 326, 322-326. 10. Fletcher, S.W., Colditz ,G.(2002) Failure of estrogen plus progestin therapy for Prevention. JAMA, 288,366­8. 11. Prentice,R.I., Manson,J.E., et al.Robert ( 2009) Benefits and risks of postmenopausal hormone therapy when it is initiated soon after menopause Am J Epidemiol. 170,12–23 12. Vickers, M.R., MacLennan, A.H., Lawton, B., et al (2007). Main morbidities recorded in the womens international study of long duration estrogen after menopause (WISDOM): a randomized controlled trial of hormone replacement therapy in postmenopausal women. BMJ, 335(7613), 239. 13. Hulley,S.,Grady,D.,Bush,T.,Furberg,C.,Herrington,D.,Riggs,B.,Vittinghoff,E., (1998).Randomized Trial of Estrogen Plus Progestin for Secondary Prevention of Coronary Heart Disease in Postmenopausal Women. JAMA. 280(7), 605-613. 14. Jankowski,C.M.,Gozansky,W.S.,Schwartz,R.S.,et.al.(2006).Effects of dehydroepiandrosterone replacement therapy on bone mineral density in older adults: a randomized, controlled trial. J Clin Endocrinol Metab., 91(8), 2986-93. 15. Grodstein,F., Manson,J.E. and Stampfer, M.J. ( 2006)hormone therapy and coronary heart disease: the role of time since menopause and age at hormone initiation. Journal of Women’s Health. 15(1), 35-44. Read More