19_ The management of hormone replacement therapy: a methodical approach

The management of hormone replacement therapy: a methodical approach

19_The management of hormone replacement therapy: a methodical approach

Abstract The role of hormone replacement therapy has continued to evolve as several recent studies have highlighted risks and benefits of use. Current research has made it possible to differentiate the risks and benefits based on individual patient profiles. This article outlines an approach to determination of hormone replacement therapy candidates, hormone selection, evaluation of risk factors, implementation of route and dose of administration, and development of continuous evaluation of estrogen plus progestin therapy use.

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19_The management of hormone replacement therapy: a methodical approach

Hormone replacement therapy (HRT) has been a topic of much debate and constant change, particularly in the past decade. In 2002, the Women’s Health Initiative (WHI) stopped their study three years early after discovering increased breast cancer risks related to HRT use.1 This prompted both providers and patients to drastically reduce their use of HRT. The objective of this randomized-controlled study was to determine the benefits of the most commonly used estrogen plus progestin HRT at that time as a preventative health measure. Additional increased health risks were revealed in this study, including heart disease, blood clots, stroke, and myocardial infarction. After the risks of HRT were demonstrated to be greater than the benefits, the U.S. Food and Drug Administration (FDA) made the recommendation that HRT be used at the lowest effective dose for the shortest duration possible.2 The WHI study did not present the information in terms of risk-benefit ratios. In addition, the results did not reflect data regarding the different HRT routes and doses of administration available nor did they derive their data from a young population without additional risk factors. Since that time, a number of studies regarding the risks and benefits of various hormone therapies have been published, some supporting the WHI findings and others negating them. These conflicting results make it challenging for both patients and providers to determine the safety of HRT. Much of the uncertainty lies in the fact that the data differs depending on the hormones involved, the dose of therapy, the route of therapy, and the patient’s profile. Some practitioners remain strong advocates of HRT, while others are resistant to using it due to the risks. Hormone replacement therapy, however, is indicated as the standard of care for the management of menopausal women experiencing moderate-to-severe vasomotor symptoms.2 The challenge for practitioners lies in determining which women are candidates for therapy and knowing how to manage their therapy over time, based on their risk profiles. Benefits and risks will differ for individuals depending on their symptoms, age of and reason for menopause 2

19_The management of hormone replacement therapy: a methodical approach

onset, heath risks, and hormone regimen. Providers can benefit from using a methodical approach to make sound choices regarding the challenges involved in the management of HRT.

Step one: identify the candidates If the patient is symptomatic, how severely do her symptoms affect her quality of life? Hormone replacement therapy is indicated for treating vasomotor and urogenital symptoms of menopause that occur with the diminished production of sex hormones by the ovaries. The diminished production of estrogen is responsible for the majority of menopausal symptoms. It helps regulate a wide range of bodily functions and maintains the integrity of structures such as the bladder, vagina, bones, and skin. In the estrogen-deficient state of menopause, women may experience hot flashes, insomnia, depression, vaginal dryness, loss of libido, and bladder irritability. The degree to which women experience these symptoms ranges in severity. Some women may not experience any symptoms, while other women’s symptoms may be debilitating. The American Association of Clinical Endocrinologists states that 85% of menopausal women experience symptoms.3 Severity also depends on the woman’s lifestyle. For example, while hot flashes may be bothersome to many women, other common symptoms, such as vaginal dryness resulting in dyspareunia, may not affect a woman who is no longer sexually active. There are some external circumstances that dictate the degree to which symptoms are experienced. Women who undergo bilateral oophorectomy at a premenopausal age will often respond with more severe symptoms than a woman who achieves natural menopause. Their bodies do not have time to adjust to the gradual decline of estrogen production that occurs during perimenopause. This sudden cessation in estrogen is often dramatic. In addition to severity, the duration women experience symptoms can also span a wide range, from a few months to several years. The average age of menopause in the United States is 51. 3

19_The management of hormone replacement therapy: a methodical approach

Statistics report that most women’s symptoms will abate within 5 years of onset.3 However, perimenopause may begin as early as age 35-40.3 A woman who goes through surgical menopause in her 20s may also experience symptoms longer than the average woman. Ultimately, the severity and duration of menopausal symptoms are highly variable from one woman to another, and it is symptom intolerability that necessitates HRT initiation. Current guidelines from the National Guidelines Clearinghouse not only recommend that HRT be offered to treat vasomotor symptoms of menopause but also for premature ovarian failure and surgical menopause, regardless of symptoms. They recommend that these women be offered HRT until the age of natural menopause, due to the benefits of estrogen in the body.4

Step two: determine the therapeutic components The next step involves determining whether the patient will need estrogen plus progestin, unopposed estrogen, or unopposed progestin. The most frequently used regimen is the combination of estrogen plus progestin, commonly referred to as HRT. Progestin must be combined with estrogen for women who have an intact uterus in order to decrease endometrial hyperplasia and reduce the risk of developing endometrial cancer. During the menstrual cycle, progesterone opposes endometrial proliferation caused by estrogen by promoting monthly shedding of the endometrium. Synthetic progesterone (progestin) given with estrogen in an HRT regimen acts in the same way. Providers need to be aware that the risks of using HRT are different from the risks of using unopposed estrogen or unopposed progestin.

Step three: determine the risk factors and benefits Studies have provided abundant evidence regarding the risks associated with using HRT. Estrogen receptors are present in tissues throughout the body, specifically in the reproductive 4

19_The management of hormone replacement therapy: a methodical approach

tract, cardiovascular system, brain, breasts, liver, and bones. [Figure 1] For this reason, using HRT requires that a balance of risks versus benefits be based on the patient’s profile. Hormone replacement therapy is often discouraged or contraindicated for women who have current or previous health conditions or a relevant family history regarding these organs where estrogen receptors are present. Hormone replacement therapy is not recommended for women with undiagnosed vaginal bleeding, a history of or current blood clots, a history of stroke or myocardial infarction in the past year, breast or uterine cancer, liver disease, or pregnancy. If a woman is a candidate for HRT, providers can begin utilizing what they know about the different hormone products and routes of administration to develop a regimen that minimizes her health risks and increases her health benefits. Cardiovascular Prior to the WHI, it was thought that HRT was likely to be beneficial for coronary heart disease prevention, based on several observational studies. In 2002, the WHI publicized that continuous oral conjugated equine estrogen combined with medroxyprogesterone had increased the risks for myocardial infarctions and strokes.1 Hormone replacement therapy was determined to be inappropriate for the primary prevention of heart disease. The coronary heart disease rates were low; however, the risk was statistically significant at an increase of 29% from those in the placebo group (p = 0.05), most due to nonfatal myocardial infarctions.1 Stroke rates increased 41% compared to the placebo group.1 It was noted that the majority of the subjects in this study started HRT more than 10 years after the onset of menopause. Later studies suggest that the increased risk for heart disease is primarily an issue of advanced age.5 This is in reference to women who start HRT at the age of 60 years or older or women who experience menopause more than 10 years prior to beginning HRT. The same study stated that the risk for coronary events actually decreases when therapy is started in younger women at the onset of menopause compared to women who do not use any HRT. This study also acknowledges that the 5

19_The management of hormone replacement therapy: a methodical approach

risks are greatest within the first year of starting therapy. Similarly, the WHI noted the risks to be equal to that of the placebo group after 2 years of therapy.1 These studies emphasize the importance of obtaining a detailed history pertaining to age, onset of menopause, duration of HRT use, and cardiovascular risk factors. In a 2006 study published in the American Journal of Hypertension, transdermal HRT was shown to be more beneficial than oral therapy in regards to blood pressure.6 The study found that the renin-angiotensin system is unaltered with transdermal therapy, whereas Angiotensin II levels are increased with oral therapy. Angiotensin II plays an important role in the pathophysiology of hypertension, cardiac hypertrophy, congestive heart failure, and coronary heart disease. The results demonstrate that diastolic and mean blood pressure are lower with transdermal HRT use in normotensive postmenopausal women and are unchanged in oral therapy users. This is one of the cardiovascular risk factors to consider when choosing the appropriate route of administration of HRT for a patient. Cholesterol, another component of cardiovascular health relevant to HRT, is affected by the amount of estrogen present. As women reach menopause, the deficiency of estrogen causes their cholesterol levels to increase, which promotes heart disease. Components of cholesterol are improved with HRT, depending on the route of administration. One study reports that oral HRT decreases total cholesterol but also decreases high density lipoprotein cholesterol.7 Another study shows that transdermal HRT is superior to oral therapy in improving high density lipoprotein cholesterol and triglycerides.8 Both therapies show improvement in total cholesterol and low density lipoprotein cholesterol. It is advisable to evaluate patients’ lipid profile before choosing a route of administration in the event that dyslipidemia can be improved with HRT use. Risk of venous thromboembolism is another reflection of cardiovascular health that needs evaluation for HRT candidates. The WHI results showed increased risks for venous 6

19_The management of hormone replacement therapy: a methodical approach

thromboembolism by 200% compared to the placebo group.1 The risks were greater for women with increasing age, obesity, and factor V Leiden mutations. A separate study proposes that thromboembolic risks are often indicated by reduced fibrinolytic activity, the presence of inflammatory markers, and increased coagulation.7 This study found that oral HRT improves fibrinolytic activity, activates inflammatory factors, and does not show activation of coagulation factors. Fibrinolytic activity is a risk factor for cardiovascular disease that naturally increases with menopause. C-reactive protein is one of the main inflammatory markers that also indicates an increased risk of heart disease and induces atherogenesis when elevated. Its activation has been associated with the increase in thrombotic events and strokes with HRT use. Results from another study provide evidence that C-reactive protein rises with oral therapy but not with transdermal therapy.9 Coagulation factors, another thromboembolic risk when elevated, are synthesized primarily in the liver. Transdermal therapy, which does not undergo hepatic metabolism, has little effect on coagulation. Multiple studies suggest that the risks outweigh the benefits of using oral therapy for women with underlying cardiovascular disease, although transdermal therapy may be a reasonable alternative. Hepatic function Liver disease is one of the previously mentioned FDA contraindications against using HRT.2 This is relevant to route of administration, because oral HRT undergoes first-pass metabolism in the liver, whereas transdermal HRT does not.7 The first-pass effect is largely responsible for the side effects one experiences from therapy. Intolerable side effects are a legitimate reason for switching someone on oral HRT to a transdermal route. Osteoporosis Total fracture incidence in the WHI study was reduced by 24% of that of the placebo group.1 Guidelines recognize that non-hormonal therapies are available for the treatment of osteoporosis. Nevertheless, HRT is indicated for osteoporosis or high risk of osteoporosis when a woman has coinciding menopausal symptoms or cannot tolerate non-hormonal 7

19_The management of hormone replacement therapy: a methodical approach

therapies.4 The estrogen-deficient state of menopause causes a reduction in bone density, leading to an increased risk for osteoporosis and osteoporosis-related fractures. Low doses of HRT, even those lower than what is used for symptomatic relief, show efficacy in preserving bone mass. Both transdermal and oral therapies demonstrate similar benefits for osteoporosis prevention. Breast cancer When the WHI was stopped in 2002, it was primarily due to findings that women using estrogen plus progestin had surpassed the endpoint boundary for increased breast cancer risk within 5 years. The increase was 26% higher than the placebo group.1 The WHI noted that progestin had caused an increase in breast density and proliferation of estrogendependent mammary tissue, affecting detection of cancer with mammograms. The National Guidelines Clearinghouse published that the increased risk was less than that of developing breast cancer from obesity or smoking.4 Current findings in 2010 presented further follow-up of the women involved in the original WHI trial regarding the effects of HRT on breast cancer. Data reveal that not only are the risks for invasive breast cancer increased, but the breast cancers are more likely to be node-positive and associated with greater mortality than previously realized.10 At this point, the WHI has concluded that a safe interval for using combined hormone therapy cannot be defined. Practitioners should note that these results are specific to combined oral therapy and to an elderly population with various risk factors. Decisions to continue using HRT should take into account the indications for HRT, the recommended dose and length of time for use, patient risk factors, and the comfort of use by both the patient and provider. Endometrial cancer Studies show that endometrial cancer is primarily associated with the use of unopposed estrogen. There were no increased risks of endometrial cancer during the WHI trial.1 Recommendations remain that progestin with estrogen is necessary for all women with an intact uterus.4 Colorectal cancer Evidence from the WHI report in 2002 demonstrated that there was a 8

19_The management of hormone replacement therapy: a methodical approach

decreased incidence of colon cancer with HRT by 37%.1 After continued follow-up in 2009, they changed their statement to say that there is no protective effect on colorectal cancer.11 Hormone replacement therapy is not indicated for the prevention of colon cancer.

Step four: determine the appropriate regimen Route of administration Providers cannot change their patients’ family histories, and while they can encourage their patients to adhere to healthy lifestyle choices, this is in hands of the patients themselves. Providers do have a great deal of power in limiting the risks and increasing the benefits from HRT when it comes to the route of administration prescribed. As previously mentioned, HRT can be administered either orally or transdermally. Each affects the body in slightly different ways. While oral therapy is primarily in the form of a tablet, transdermal therapy can be given as patches systemically or as vaginal creams, rings, tablets, and gels locally. Vaginal creams, rings, tablets, and gels are effective for treating vaginal symptoms, but they are not available in high enough doses to provide any benefit for treating or preventing osteoporosis. Symptomatic women with no known health risks may benefit from either oral or transdermal systemic therapy that helps prevent osteoporosis as well as treat their menopause symptoms. A woman with multiple risk factors, such diabetes, deep vein thromboses, and hepatitis, who is still sexually active and has symptoms of dyspareunia and frequent urinary tract infections, may be best suited for a vaginal local therapy. The women who fall somewhere in between are more challenging to match to an appropriate therapy plan. A thorough review of each woman’s menopause history and risk factors will lead the practitioner to make prudent choices when developing a regimen for HRT. Many patients will present to providers as new patients already on HRT that warrant changes. For example, if a woman has been diagnosed with osteopenia but has a local skin reaction to the transdermal patch, oral therapy is a reasonable switch that will 9

19_The management of hormone replacement therapy: a methodical approach

still provide her with the benefit of protection against osteoporosis. A thorough evaluation of the complete health profile will lead providers to help improve their patients’ quality of life as well as minimize their health risks. Dose Choose the lowest possible dose. Current FDA indications for HRT are to use the lowest effective dose for the shortest duration possible.2 Low doses of HRT equate to fewer side effects and fewer risks in most cases. The dosage used in the WHI and in many other HRT regimens in the past have now proven to be effective at lower doses than previously thought.

Step five: develop a long-term plan Hormone replacement therapy necessitates a regular review of risks versus benefits for each patient. Scheduled follow-ups and yearly check-ups should involve updating patient information. The effectiveness of the current dose and route of administration as well as tolerability of therapy should be discussed. Side effects may include headaches, nausea, leg cramps, breast tenderness, fluid retention, fatigue, irritability, melena, and monthly bleeding. These side effects may be due to either the dose of progestin or estrogen in the regimen or the route of therapy. Health risks often change with age. Patients need to have timely preventative screening tests, including mammograms, bone density scans, liver function tests, lipid panels, and blood pressure readings. Yearly checklists can be implemented into electronic medical records with templates or forms for paper charts that will reassess family history, current diagnoses, and results of lab and screenings tests. A review of lifestyle habits regarding diet, exercise, smoking, and substance abuse is also important to fully assess current health risks. Finally, a plan to attempt weaning the patient from HRT should be in place and assessed periodically, particularly after they have reached the average age of menopause.

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19_The management of hormone replacement therapy: a methodical approach

Alternatives to HRT For some patients, HRT will be contraindicated, intolerable, or undesired, despite the need for symptomatic treatment. The recommendations for menopause intervention include consideration of lifestyle modifications, hormone therapy, non-hormone therapy, and investigation of postmenopausal bleeding.4 Lifestyle modifications involve reducing core body temperature, regular exercise, weight management, smoking cessation, and avoidance of known triggers, such as hot drinks and alcohol. If HRT is contraindicated, non-hormone therapy, such as antidepressants, may be used to treat hot flashes. Other non-hormone prescription medications that have shown efficacy towards treating vasomotor symptoms include clonidine and gabapentin. Osteoporosis can be treated with bisphosphonates and selective estrogen receptor modulators. Natural medicines, such as those containing soy, black cohosh, phytoestrogens, and vitamin E have demonstrated inconclusive findings and are not currently recommended by the FDA for the use of treating symptoms of menopause. These supplements have the potential to cause harm and unless providers are trained in natural medicine, they should refer patients to providers with the appropriate training.

Conclusion Familiarity with the current research and recommendations is imperative in regards to prescribing HRT, because this is a rapidly evolving aspect of medicine. This is also an area of medicine that receives a vast amount of media coverage and involves a large number of women. Many of them have become wary, with good reason, about the ramifications of HRT use. There are several heavily researched benefits and risks to using HRT. Despite the risks associated with it, guidelines still recommend that hormone therapy be offered to patients as the most effective management for menopausal symptoms. Ultimately, using HRT is a decision to be made by the 11

19_The management of hormone replacement therapy: a methodical approach

patient with the help of the provider that requires a careful and detailed methodical assessment of individual risks versus benefits.

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19_The management of hormone replacement therapy: a methodical approach

References 1. Rossouw JE, Anderson GL, Prentice RL, et al. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women’s Health Initiative randomized controlled trial. JAMA. 2002;288(3):321–333. [seminal] 2. Menopause: medicines to help you. Food and Drug Administration Web site. http://www.fda.gov/ForConsumers/ByAudience/ForWomen/ucm118627.htm#progonly. Updated February 28, 2010. Accessed November 5, 2010. 3. AACE Menopause Guidelines Revisions Task Force. American Association of Clinical Endocrinologists medical guidelines for clinical practice for the diagnosis and treatment of menopause. Endocr Pract. 2006;12(3):315-337. 4. Vasomotor symptoms: menopause and osteoporosis update 2009. National Guidelines Clearinghouse Web site. http://www.guideline.gov/content.aspx?id=13609&search= menopause. Accessed November 5, 2010. 5. Grodstein F, Manson JE, Stampfer MJ. Hormone therapy and coronary heart disease: the role of time since menopause and age at hormone initiation. J Womens Health. 2006;15(1):35-44. 6. Ichikawa J, Sumino H, Ichikawa S, Ozaki M. Different effects of transdermal and oral hormone replacement therapy on the renin-angiotensin system, plasma bradykinin level, and blood pressure of normotensive postmenopausal women. Am J Hypertens. 2006;19(7):744749. 7. Zegura B, Guzic-Salobir B, Sebestjen M, Keber I. The effect of various menopausal hormone therapies on markers of inflammation, coagulation, fibrinolysis, lipids, and lipoproteins in healthy postmenopausal women. Menopause. 2006;13(4):643-650. 8. Samsioe G, Boschitsch E, Concin H, et al. Endometrial safety, overall safety and tolerability of transdermal continuous combined hormone replacement therapy over 96 weeks: a 13

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randomized open-label study. Climacteric. 2006;9(5):368-379. 9. Ho JY, Chen MJ, Sheu WH, et al. Differential effects of oral conjugated equine estrogen and transdermal estrogen on atherosclerotic vascular disease risk markers and endothelial function in healthy postmenopausal women. Hum Reprod. 2006;21(10):2715-2720. 10. Chlebowski RT, Anderson GL, Gass M, et al. Estrogen plus progestin and breast cancer incidence and mortality in postmenopausal women. JAMA. 2010;304(15):1684-1692. 11. Prentice RL, Pettinger M, Beresford SA, et al. Colorectal cancer in relation to postmenopausal estrogen and estrogen plus progestin in the Women's Health Initiative clinical trial and observational study. Cancer Epidemiol Biomarkers Prev. 2009;18(5):15311537.

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Figure 1. Estrogen receptor target sites Estrogen. Mayo Clinic Web site. http://mayoresearch.mayo.edu/vmiller_lab/estrogen.cfm. Accessed December 15, 2010.

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