Hormone replacement therapy, or HRT, is a type of therapy that may have major benefits such as relieving menopausal symptoms, which may include vasomotor instability, osteoporosis and fracture risk, urogenital and vaginal atrophy, low mood, and memory problems. However, research leading to conflicting results has been conducted over the course of over seventy years which shows that HRT also has primary risks. These include diseases such as breast cancer, endometrial hyperplasia, endometrial cancer, cardiovascular disease, venous thromboembolism, and stroke (Rhymer, J., 2003). This paper will focus on the various biological components used in hormone replacement therapy for menopausal and postmenopausal women, different examples of its benefits and the risks, and what the biological data implies in terms of indication or contraindication of HRT on a societal level.
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Since HRT is primarily used to treat menopausal symptoms, the biological understanding of menopause should first be explained to grasp HRT’s therapeutic benefits. Menopause is the natural cessation of the menstrual cycle that occurs in women at an average of 51.4 years of age (Bakour, S. H., & Williamson, J., 2014). There is a wide arrange of menopausal symptoms depending on sociological factors such as social class, ethnicity, and culture, that cause women to seek relief by means of HRT (Rymer, J., 2003). Menopausal symptoms tend to have a negative effect on overall quality of life (Bakour, S. H., & Williamson, J., 2014). For example, the most common, discomforting menopausal symptoms are vasomotor ones, which affect approximately 70% of women for an average of 5.2 years while 10% of women may experience them for many more years (Bakour, S. H., & Williamson, J., 2014). About 20% of women experience more severe symptoms (Bakour, S. H., & Williamson, J., 2014). Another one of the main menopausal symptoms is the decrease of bone density in women, an effect that is accelerated by estrogen deficiency, which halts or slows bone loss, resulting in osteoporosis (Barrett-Connor, E., & Stuenkel, C. A., 2001).
Prescribing HRT is considered the most effective solution for relieving menopausal symptoms, which can effectively be resolved by HRT’s replacement doses of estrogen (Bakour, S. H., & Williamson, J., 2014). The presence of disturbing vasomotor symptoms may result in sleep disruptions and contribute to the main indication for the administering of HRT (Hickey, M., Elliott, J., & Davison, S. L., 2012). Hormone replacement therapy consists of estrogen for relieving menopausal symptoms, and estrogen can also be mixed with progestogen, which binds to the progesterone receptor, for endometrial protection in affected women (Hickey, M., Elliott, J., & Davison, S. L., 2012). The most common way to take HRT is as an oral medication, which is usually administered in a pill form (Rymer, J., 2003). However, an important distinction for women to know is that the ethinyl estradiol used in HRT’s oral contraception is a synthesized form of estrogen, not the natural form of estrogen produced in ovarian production. Other forms estrogen include 17 beta-estradiol, estrone, or conjugated equine estrogen (Hickey, M., Elliott, J., & Davison, S. L., 2012). If a woman still has a uterus, it is essential for progestogen or micronized progestogen to be included for prevention of endometrial hyperplasia and cancer (Rymer, J., 2003). Progestogen is usually also administered orally (Rymer, J., 2003). During regimens of HRT, estrogen is taken daily, while progestogen may be added in combination with estradiol either in a sequential cyclical regimen or daily as a continued combined therapy (CCT) if it is required (Rymer, J., 2003). While testosterone can also be added to HRT as a supplement, it will not be covered in the information disclosed here (Bakour, S. H., & Williamson, J., 2014). Alternatively, these forms of estrogen and progestogen, as well as others, can also be taken intravaginally or transdermally (Hickey, M., Elliott, J., & Davison, S. L., 2012).
About 38% of postmenopausal women in the United States were administered HRT in 2003. For example, 46 million prescriptions of Premarin were administered in 2000, a form of HRT consisting of conjugated equine estrogens (Rymer, J., 2003). This made this form of HRT the second most frequently prescribed drug in the United States (Rymer, J., 2003). British studies that were conducted in 2003 have shown that 60% of women between 51-57 years of age have taken HRT (Rymer, J., 2003). According to these studies, 45% of women were reported to have tried HRT by the time they are 50.2 years of age (Rymer, J., 2003).
The controversial aspect of HRT primarily exists because of the many benefits and risks that are associated with taking it (Rymer, J., 2003). However, there is a large amount of complexity and uncertainty about the evidence taken from various controlled trials for HRT that have found conflicting results (Rymer, J., 2003). For example, both a multitude of beneficial effects and adverse side effects were found in the publication of the heart and estrogen-progestin replacement study (HERS) and a Women’s Health Initiative (WHI) study (Rymer, J., 2003). Some of the benefits and risks are correlated with contexts such as age, duration of treatment, and pre-existing conditions (Rymer, J., 2003).
Furthermore, there is a variety of benefits associated with taking HRT. HRT for symptom relief should be administered within the early phase of menopausal symptoms for treatment benefits (Bakour, S. H., & Williamson, J., 2014). However, for women with premature menopause (younger than 40 years of age) or early menopause (younger than 45 years of age) it is recommended that women delay until age 50 to receive HRT for vasomotor systems and bone preservation (Hickey, M., Elliott, J., & Davison, S. L., 2012). The reason for this is that women between 50 to 59 years of age tend to respond with more of the benefits from HRT and less of the risks based on data collected from the Women’s Health Initiative study the prospective observational Nurse’s Health Study (Hickey, M., Elliott, J., & Davison, S. L., 2012). Conversely, HRT is generally not recommended for women over 60 years of age because the probability of HRT’s risks are increased this late after menopause begins (Hickey, M., Elliott, J., & Davison, S. L., 2012). Thus, the current guidelines for HRT recommend treatment for most symptomatic women between 50-59 years of age, but taking HRT for more than five years is not recommended (Hickey, M., Elliott, J., & Davison, S. L., 2012).
Vasomotor symptoms include often uncomfortable hot flushes and night sweats in menopause, and HRT is the most effective treatment relieving them (Hickey, M., Elliott, J., & Davison, S. L., 2012). The Women’s Health Initiative and prospective observational Nurses’ Health Study conducted some of the largest randomized and controlled trials of HRT versus placebo in American women ages 50-59 years (less than 10 years after menopause). Based on their results, there was a major reduction in the frequency of hot flushes by approximately 18 per week with the severity of hot flushes decreased by 87% in contrast with placebo (Hickey, M., Elliott, J., & Davison, S. L., 2012). Therefore, the forms of HRT, both estrogen and estrogen combined with progestogen, have shown remarkable benefits for the treatment of vasomotor symptoms from menopause (Hickey, M., Elliott, J., & Davison, S. L., 2012). HRT has been approved and labelled by the FDA for its application in treating vasomotor symptoms based on substantial evidence of these resulting benefits (Biscup, P., 2003). According to thirteen randomized clinical trials, hormone replacement therapy may also induce a causal effect in that its treatment of vasomotor and urogenital symptoms may improve various other menopausal symptoms (Rymer, J., 2003). By relieving hot flushes, one of the vasomotor symptoms listed in menopause, sleep quality and low mood may subsequently be improved (Rymer, J., 2003). Overall, the estrogen used in HRT has proven to temporarily enhance the quality of life in women with menopausal symptoms (Rymer, J., 2003).
Some other methods of treatment include tibolone, a non-hormonal alternative to HRT for treating menopausal symptoms (Rymer, J., 2003). Tibolone is an oral steroid that is synthesized with estrogenic, androgenic, and progestogenic ingredients that can be substituted as another form of HRT (Bakour, S. H., & Williamson, J., 2014). There has not been as much verification of effectiveness from the studies of tibolone as there has been of the typical HRT, which contains some combination of estrogen and progestogen (Hickey, M., Elliott, J., & Davison, S. L., 2012). However, one large, multicenter, randomized, double blind, and controlled trial has demonstrated some effectiveness of tibolone when as much as 1 mg of oral estradiol was used to reduce occurrences of hot flushes in postmenopausal women between 45-65 years of age (Hickey, M., Elliott, J., & Davison, S. L., 2012). Also, tibolone reduced bleeding within the first three months of treatment, reduced breast tenderness, and improved sexual function (Hickey, M., Elliott, J., & Davison, S. L., 2012). Gabapentin is a non-hormonal alternative to HRT that has proven to be equally as effective as low dose estrogen for treating vasomotor symptoms, whereas Clonidine is mildly effective (Hickey, M., Elliott, J., & Davison, S. L., 2012). The levonorgestrel-releasing intrauterine system Mirena has been licensed and available for four years in the United Kingdom, along with estrogen replacement therapy, since the time this article was published in 2003 (Rymer, J., 2003).
Aside from relieving vasomotor symptoms, the other main reason for administering hormone replacement therapy is the prevention or management of osteoporosis (Rymer, J., 2003). After 35 years of age, bone mass in men and women is reduced by about 1% each year (Rymer, J., 2003). The decrease of bone density is accelerated in women within the first three to four years after menopause, and a third of these women are at a larger risk of osteopenia, a form of decreased bone density that could lead to a higher risk of fracture (Rymer, J., 2003). According to data collected from randomized controlled trials, HRT has been shown to reduce fracture risk as well as bone loss in the vertebral spine by 50% and in the femur neck by 30% (Rymer, J., 2003). However, the prevention of bone loss may also apply at lower percentages in women older than 60 years of age. According to the Women’s Health Initiative (WHI) study on the reduction of a hip fracture using HRT, bone loss resumes within a year after stopping hormone replacement therapy, and bone turnover occurs at the same level seen in untreated women between three to six months after receiving therapy (Rymer, J., 2003). Furthermore, reduction of fracture risk alone may not be an appropriate indication for administering of HRT (Hickey, M., Elliott, J., & Davison, S. L., 2012). Alternatives for preventing fracture risks in women with low bone mineral density may include non-hormonal therapies that are equally as effective as HRT (Rymer, J., 2003). Some examples of non-hormonal therapies for reduction of fracture risks include bisphosphonates and selective estrogen receptor modulators (Rymer, J., 2003).
Another beneficial set of data drawn from thirty observational studies of HRT, is that estrogen lowers the risk of heart disease in postmenopausal women (Barrett-Connor, E., & Stuenkel, C. A., 2001). These studies demonstrated that estrogen caused a 40-50% reduction in the risk of coronary heart disease (CHD) in women, whereas estrogen has been shown to reduce disease and death from coronary heart disease by 30-50%, which would consist of a greater benefit if progestogens were not added to prevent women from developing endometrial disease (Rymer, J., 2003). Since cardiovascular disease is highly improbable in women before menopause, estrogen deficiency is a strongly implied cause for heart disease (Rymer, J., 2003).
As previously stated, the positive effect of HRT on heart disease has been correlated with other variables such as lipids and vascular reactivity (Barrett-Connor, E., & Stuenkel, C. A., 2001). Some of the main cardiovascular benefits of estrogen are achieved through the following influences: reduction of atherosclerosis, increase of HDL-cholesterol (high-density lipoprotein-cholesterol), decrease of LDL-cholesterol (low-density lipoprotein-cholesterol), promotion of coronary artery vasodilation, prevention of platelet aggregation, decrease of lipoprotein-a, and inhibition of low-density lipoprotein-cholesterol oxidation (Bakour, S. H., & Williamson, J., 2014). It should be noted that these observational studies were conducted on healthy women taking HRT rather than women with pre-existing conditions or diseases, a crucial factor that critics claim may have affected the results of these studies (Bakour, S. H., & Williamson, J., 2014). However, despite this fact, a large number of clinicians have advertised and administered HRT as a preventative therapy because of the decreased cases of heart disease found with its usage (Bakour, S. H., & Williamson, J., 2014).
The remaining benefits of HRT include reduction of urogenital atrophy or atrophic vaginitis, reduced risk of colon or colorectal cancer, protection against loss of connective tissue, improvement of low mood, prevention of memory loss, delay in the onset of Alzheimer’s disease, and improved cognitive functioning (Rymer, J., 2003). The type of HRT used in the treatment of atrophic vaginitis, i.e. thinning, drying, and inflammation of the vaginal walls, is topical estrogen, which initiates cornification, developing tough protective layers from squamous epithelial cells, and regenerates the vaginal epithelium without the need for progestogens (Bakour, S. H., & Williamson, J., 2014). Thus, moderate to high doses of topical estrogen improve lubrication and sexual functioning of the vagina, which can then reduce symptoms such as urgent urinating and recurring urinary tract infections (Bakour, S. H., & Williamson, J., 2014). Vaginal symptoms such as the ones mentioned can persist despite the application of adequate systemic HRT, and in this case, topical and systemic HRT are mandated for treatment (Bakour, S. H., & Williamson, J., 2014). Large randomized controlled trials have also confirmed that HRT remarkably improves upon vaginal dryness and sexual function, which can consequently improve sleep, alleviate muscle aches and pains, and improve overall quality of life in women who carry these symptoms (Hickey, M., Elliott, J., & Davison, S. L., 2012).
Although hormone replacement therapy may help in improving libido, vaginal symptoms alone do not warrant the prescription of HRT, as these symptoms can be treated using local estrogens (Biscup, P., 2003). Alternatively, non-hormonal options for atrophic vaginitis include vaginal lubricants and moisturizers, but studies have not offered sufficient evidence that these alternatives offer the prolonged benefits found with the usage of vaginal estrogen (Hickey, M., Elliott, J., & Davison, S. L., 2012). In regards to the main risks involved with the usage of topical estrogen, the benefits to the genitourinary tract as well as improved sexual intimacy may be greater than any risk of breast cancer (Rymer, J., 2003).
In a Women’s Health Initiative randomized control trial of 10,000 women taking HRT in contrast with the placebo group, HRT was confirmed to reduce the risk of colorectal, or colon, cancer (Rymer, J., 2003). The results indicated six fewer colorectal cancers per year out of the 10,000 women taking HRT (Rymer, J., 2003). Also, more than ten observational studies have shown a decreased risk of colorectal cancer in women taking HRT (Barrett-Connor, E., & Stuenkel, C. A., 2001). However, the reduction of colorectal cancer is not considered to be an indication for administering HRT as a preventative for this disease because there isn’t enough data to verify this beneficial side effect of HRT (Barrett-Connor, E., & Stuenkel, C. A., 2001).
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Furthermore, HRT has also been observed to provide neuroprotective benefits such as sustained cognitive functioning, improvement upon low mood, prevention of memory loss, and reduction or delay of Alzheimer’s disease (Rymer, J., 2003). According to more than half of observational studies from two large randomized trials, women who take estrogen maintain or improve cognitive functioning more than women who do not (Rymer, J., 2003). Risk of Parkinson’s disease may also be prevented by HRT, but this benefit was seen in young, healthy menopausal women, so more studies are also needed on neuroprotective factors, especially on menopausal women without the healthy disposition found in women in these studies to contrast results (Rymer, J., 2003).
In opposition to the various benefits of HRT, there are also important risks that have been found to be associated with its treatment, such as breast cancer, endometrial hyperplasia, and endometrial cancer. In 1997, the Collaborative Group from Oxford reanalyzed 51 observational studies of HRT and breast cancer, including 52,705 women with breast cancer, to discover that women who had been taking HRT for five years or more had a greater risk of developing breast cancer (Barrett-Connor, E., & Stuenkel, C. A., 2001). Four or five years of a woman using HRT was found to increase risk of breast cancer, and this risk was heightened in women who used estrogen mixed with progestogen rather than using estrogen alone (Barrett-Connor, E., & Stuenkel, C. A., 2001). By using this large meta-analysis of data, the risk of breast cancer was found to increase by 2.3% per year of using HRT (Rymer, J., 2003). According to a Women’s Health Initiative study, there was a 15% increase in invasive breast cancer in women taking estrogen with progestogen for less than five years and a 53% increase in those taking it for more than five years (Rymer, J., 2003). However, duration of usage combined with potentially recurrent symptoms, which up to 50% of women experience after discontinuation of HRT, tend to have the greatest influences on risk (Hickey, M., Elliott, J., & Davison, S. L., 2012).
The controversy associated with the increased risk of breast cancer due to HRT exists because different studies have found opposing information. While some observational studies have shown an increased risk of breast cancer in women who took HRT, other observational studies, including ones conducted on women with a family history of breast cancer, show no increased risk of breast cancer, and many researchers currently tend to dismiss studies that display conclusions of an increased risk, despite evidence such as Nurses’ Health Study (Bluming, A. Z., & Tavris, C., 2009). Risk of breast cancer has been found to be insignificant because using data found from a worst-case analysis, researchers have concluded that a 50-year-old woman taking estrogen and progestin for ten years had a 4% risk of breast cancer while using HRT, while her breast cancer risk without taking HRT was only 2% (Bluming, A. Z., & Tavris, C., 2009). This evidence may have been exaggeratedly stated by data-reporters as a “doubling” of risk of breast cancer due to HRT (Bluming, A. Z., & Tavris, C., 2009). Other observational studies have shown increased survival rates of women who take estrogen replacement therapy (ERT), including decreased death rates from breast cancer (Bluming, A. Z., & Tavris, C., 2009).
Furthermore, there is a large volume of other results that have found that if six million women in the United States have used HRT for five years, then over 24,000 additional cases of breast cancer would develop every year, and thus, it is essential that every woman’s individual risk as well as a family history of breast cancer is assessed before administering HRT (Biscup, P., 2003). Some studies have shown that women who use HRT for more than five years are at a much higher risk of breast cancer, and further HRT is contraindicated in this case (Biscup, P., 2003). Results have shown that other health factors may also apply to this such as diet, exercise, dyslipidemia or diabetes, or smoking (Biscup, P., 2003).
Another correlation has been made between women with an intact uterus taking HRT and risk of endometrial hyperplasia and endometrial cancer (Hickey, M., Elliott, J., & Davison, S. L., 2012). This relationship has been established since the 1970s (Barrett-Connor, E., & Stuenkel, C. A., 2001). According to results taken from a PEPI trial, estrogen alone was found to increase endometrial hyperplasia at a rate of 10% per year and increased the risk of cancer in some women (Barrett-Connor, E., & Stuenkel, C. A., 2001). Endometrial cancer was increased by 4-5 times for five years and by ten times for ten years of using unopposed estrogen (Barrett-Connor, E., & Stuenkel, C. A., 2001). However, usage of progestogen with HRT or the alternative prescription tibolone does not increase the risk of endometrial hyperplasia or endometrial cancer, but progestogen’s protection diminishes with long-term usage of sequential regimens, especially after five years of use (Hickey, M., Elliott, J., & Davison, S. L., 2012). Furthermore, continuous progestogen regimens can also assist in correcting complex hyperplasia that may occur within sequential therapy, keeping the endometrium suppressed in the longer term (Rymer, J., 2003).
The correlation between HRT and cardiovascular disease is controversial and largely based on timing, duration, and preceding heart conditions (Barrett-Connor, E., & Stuenkel, C. A., 2001). Increased risk of cardiovascular disease has been found with routine acceptance of use of HRT when the largest HRT randomized clinical trial was conducted in 2002 which considered long term usage of estrogen and progestin (Krieger, N. et. al, 2005). In the year 2000, Women’s Health Initiative investigators conducted a trial on 27,348 women, finding small increased risk of cardiovascular disease within the first year of administering HRT, especially in women over 60 years of age since they are more likely to show signs of cardiovascular disease, although the cardiovascular systems in younger postmenopausal women may be benefited by taking HRT (Barrett-Connor, E., & Stuenkel, C. A., 2001). Reanalysis of the Women’s Health Initiative study in 2007 found that the taking of HRT by women within ten years of menopause was correlated with less risks as well as an overall reduction in cardiovascular events, whereas women who took HRT for more than twenty years after menopause were found to become more susceptible to cardiovascular risk (Bakour, S. H., & Williamson, J., 2014). Although it has not been proven, it is strongly implied that estrogen deficiency may increase the risk of cardiovascular disease in women because cardiovascular disease rarely affects women before menopause (Rymer, J., 2003). The correlation between estrogen levels and heart disease in postmenopausal women has been suggested by more than 30 observational studies, which have found that estrogen has multiple health benefits for preventing heart disease in correlation to lipids and vascular reactivity (Barrett-Connor, E., & Stuenkel, C. A., 2001).
Risks of deep vein thrombosis and pulmonary embolus have also been shown to increase in women who take HRT (Rymer, J., 2003). Thrombosis risk from HRT is usually recorded as having occurred within the first year of usage. However, dosage size, type, route of application, and the usage of progestogen combination may also contribute to this risk of HRT (Bakour, S. H., & Williamson, J., 2014). Lower doses of HRT as well as replacing oral treatment with transdermal treatment, which is the primary treatment method in medical conditions, may reduce the risk of venous thromboembolism (VTE) (Bakour, S. H., & Williamson, J., 2014). However, women who are sedentary, overweight, and smokers have an increased risk of VTE before receiving HRT (Bakour, S. H., & Williamson, J., 2014).
Statistics based on 1,000 European women between 50-59 years of age show that five were at risk for VTE, seven were at risk for VTE when having taken five years of estrogen only, and twelve were at risk for VTE after having taken estrogen and progestogen for five years (Bakour, S. H., & Williamson, J., 2014). Other studies show that women taking HRT, especially for five years or more, increases the risk of VTE two-fold in contrast with those who weren’t prescribed HRT, but family history of thromboembolic disease, severe varicose veins, obesity, surgery, and trauma, as well as prolonged bed rest and age are all factors that put women at a greater risk (Bakour, S. H., & Williamson, J., 2014). Further observational studies on VTE have determined that postmenopausal women who took HRT may have a 2-4 fold increase in VTE, which was found in a trial of 1,000 women (Barrett-Connor, E., & Stuenkel, C. A., 2001). About 1 in 250 women who had received HRT developed VTE, and this risk was heightened in women with a lower-extremity fracture, cancer, and 90 days after inpatient surgery or non-surgical hospitalization (Barrett-Connor, E., & Stuenkel, C. A., 2001). Finally, observational studies have also shown that estrogen therapy increased other risks such as blood clots, strokes, and gallbladder disease (Biscup, P., 2003). Furthermore, the risk of stroke increases with age and usually occurs in women over 60 years of age when using tibolone or HRT (Hickey, M., Elliott, J., & Davison, S. L., 2012). Transdermal HRT at doses of 50 μg or less may reduce the risk of stroke (Hickey, M., Elliott, J., & Davison, S. L., 2012).
Education on the results taken from trials done on women using HRT has been shown to affect women’s decision on continuing or discontinuing HRT, demonstrating the influential effects of conducting more studies and publicly posting their conclusions (Ness, J., Aronow, W. S., Newkirk, E., & Mcdanel, D., 2005). Women’s Health Initiative conducted and publicized trial results from a study on 1,000 postmenopausal women with an average range of 57-73 years of age to find the aftereffects of having published results from a trial in July of 2002 to record how prescriptions and applications of HRT may have changed due to updated information on the risks of HRT (Ness, J., Aronow, W. S., Newkirk, E., & Mcdanel, D., 2005). The data showed that 445 (45%) of the women had used or were still using HRT at the time of conducting this review. 159 (36%) of the 445 women using HRT were still using it, and 286 (64%) of the 445 women using HRT had decided to discontinue usage of HRT (Ness, J., Aronow, W. S., Newkirk, E., & Mcdanel, D., 2005). Although 181 (63%) of the women had ceased usage of HRT after the Women’s Health Initiative publication, 136 (48%) of the women listed the 2002 study as the main reason for discontinuation (Ness, J., Aronow, W. S., Newkirk, E., & Mcdanel, D., 2005). The 159 women still using HRT after these studies listed their mains reasons as follows: relief from severe menopausal symptoms in 39 women (25%), osteoporosis or osteopenia in 31 women (20%), and patient preference in 20 women (13%) (Ness, J., Aronow, W. S., Newkirk, E., & Mcdanel, D., 2005).
In conclusion, although there are many benefits and risks to hormone replacement therapy, there is still much study needed to be done to publicize more certain answers on HRT. Results have shown that duration, i.e. about five years, is a primary factor in taking HRT in that most serious risks have been shown to occur after this time. During up to five years of taking HRT are when most of the benefits start to show, such as reduction of vasomotor symptoms, reduction of osteoporosis, vaginal atrophy, and boost of cognitive functioning. However, within and especially after five years of taking HRT increases the probability of its risks, such as breast cancer, cardiovascular disease, deep vein thrombosis, stroke, etc. HRT’s risks outweigh its benefits, there is plenty of empirical evidence from various studies that suggest the contrary. Overall, individual risk, family history, and age, i.e. time of and after having started menopause are all crucial factors in considering whether HRT is indicated or contraindicated. Thus, more data and studies should be investigated to educate women and circulate information about the many benefits and potentially harmful effects to this complex form of treatment. Previous controlled trial results from the Women’s Health Initiative have been proven to influence women’s decisions on whether or not they should take hormone replacement therapy. Thus, it may be beneficial for WHI to receive financial investments if needed so that more randomized controlled studies can be conducted with published results on HRT since this has been proven to assist women in making their decisions regarding HRT.
- Bakour, S. H., & Williamson, J. (2014). Latest evidence on using hormone replacement therapy in the menopause. The Obstetrician & Gynaecologist,17(1), 20-28. doi:10.1111/tog.12155
- Barrett-Connor, E., & Stuenkel, C. A. (2001). Hormone replacement therapy (HRT)— risks and benefits. International Journal of Epidemiology,30(3), 423-426. doi:10.1093/ije/30.3.423
- Biscup, P. (2003). Risks and benefits of long-term hormone replacement therapy. American Journal of Health-System Pharmacy,60(14), 1419-1425. doi:10.1093/ajhp/60.14.1419
- Bluming, A. Z., & Tavris, C. (2009). Hormone Replacement Therapy: Real Concerns and False Alarms. The Cancer Journal,15(2), 93-104. doi:10.1097/ppo.0b013e31819e332a
- Hickey, M., Elliott, J., & Davison, S. L. (2012). Hormone replacement therapy. Bmj,344(Feb16 2). doi:10.1136/bmj.e763
- Krieger, N. et. al (2005). Hormone replacement therapy, cancer, controversies, and women’s health: Historical, epidemiological, biological, clinical, and advocacy perspectives. Journal of Epidemiology & Community Health,59(9), 740-748. doi:10.1136/jech.2005.033316
- Ness, J., Aronow, W. S., Newkirk, E., & Mcdanel, D. (2005). Use of Hormone Replacement Therapy by Postmenopausal Women After Publication of the Women’s Health Initiative Trial. The Journals of Gerontology Series A: Biological Sciences and Medical Sciences,60(4), 460-462. doi:10.1093/gerona/60.4.460
- Rymer, J. (2003). Making decisions about hormone replacement therapy. Bmj,326(7384), 322-326. doi:10.1136/bmj.326.7384.322
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