Note: This guideline has been updated. The National Guideline Clearinghouse (NGC) is working to update this summary. The recommendations that follow are based on the previous version of the guideline.
Note from the National Guideline Clearinghouse (NGC) and the Institute for Clinical Systems Improvement (ICSI): For a description of what has changed since the previous version of this guidance, refer to Summary of Changes - October 2006.
The recommendations for menopause and hormone therapy (HT) are presented in the form of an algorithm. An algorithm is provided for Menopause and Hormone Therapy (HT): Collaborative Decision-Making and Management with 8 components, accompanied by detailed annotations. Clinical highlights and selected annotations (numbered to correspond with the algorithm) follow.
Class of evidence (A-D, M, R, X) and conclusion grade (I-III, Not Assignable) definitions are provided at the end of the "Major Recommendations" field.
Clinical Highlights
- There are many effective options to be considered for the relief of menopausal symptoms; although hormone therapy (HT) is often the most effective treatment, it is not always necessary. (Annotation #2a)
- Periodically re-evaluate women on HT to determine if it is still indicated, particularly if there have been changes in their health status. (Annotations #2b, 7)
- Women who have recently discontinued HT are at risk for rapid bone loss; they must be identified and monitored appropriately to ensure continued bone health. (Annotations #2b, 2c)
- At this time, the role of HT in disease prevention has been all but eliminated in current practice. (Annotation #2c)
- The well-publicized results of several recent clinical trials have resulted in increased apprehension about HT among both patients and providers. It is unlikely that definitive information or consensus will be available anytime soon. (Annotations #1, 3)
- The exact risks associated with HT, as well as possible side effects, may not be fully defined, but they cannot be dismissed and must always be considered and discussed as part of the collaborative decision-making process. (Annotations #3, 4, 6a)
- Careful consideration and in-depth discussion are required whenever the initiation or continuation of HT is considered; help each woman clarify her individual values and priorities so that she may decide how important each of the potential benefits and risks of HT is to her unique situation. (Annotation #4)
- Provide support and encouragement, through accessibility and close follow-up, for women who have recently initiated HT. (Annotations #6a, 7, 8)
Menopause and Hormone Therapy (HT): Collaborative Decision-Making and Management Algorithm Annotations
- Discuss Midlife Health Issues and Menopause
Key Points:
- Consider initiating discussions about menopause and HT starting at age 40.
- Be alert to subtle signs of menopause, including mood and sleep disturbances.
- Laboratory testing is usually not necessary to establish menopausal status.
- In counseling patients, distinguish between short-term hormone therapy for menopausal symptom relief (minimal risk) and long-term hormone therapy for the prevention of chronic disease (rarely initiated).
Consider initiating a discussion about these issues as part of routine health maintenance visits with women 40 years of age or older. Many women wish to begin this discussion well before menopause.
For women on HT, regularly review and discuss its use. (See also Annotation #2b, "Discuss Options for Long-Term HT Users; Ensure Continued Bone Health".)
There are three distinct areas for discussion and decision-making related to midlife health issues. These are reflected in the organization of this guideline:
- Options for menopausal symptom relief
- Options for women who have been long-term HT users and who seek advice about continuing, stopping, or modifying their regimen
- Options for risk factor modification and disease prevention
Encourage Healthy Lifestyles
Always emphasize healthy lifestyles and lifestyle modifications as the most important first step in both menopausal symptom relief and disease prevention.
Clarify Menopausal Status; Be Alert to Subtle Signs of Menopause
In addition to inquiring about common menopausal symptoms, also ask about irritability, anxiety, sleeplessness, or agitation. Some women may not consider these symptoms to be menopausal or may be embarrassed to volunteer information about them.
Laboratory Testing Is Usually Not Necessary to Establish Menopausal Status
Clarifying whether or not a woman is perimenopausal is usually a clinical diagnosis and laboratory testing is not required. Serum levels of follicle stimulating hormone (FSH) do not correlate with either intensity or frequency of hot flashes; it is fluctuation in estrogen levels that seems to be of greater significance.
For women with apparent menopausal symptoms who are younger than average (less than 35), or who continue to have apparently regular menses, testing may be useful. Measure both FSH and estradiol (E2).
Testing may be most useful for the older woman (over age 50) still on oral contraceptives (OCPs) who is interested in confirming that OCPs can be discontinued. FSH levels can fluctuate during the early perimenopause; therefore, an isolated FSH level, particularly if only borderline elevated, is not totally confirmatory. Alternatively, although estradiol levels can occasionally remain elevated after discontinuation of OCPs, a low estradiol level is a reliable confirmation of menopause.
Currently, there is insufficient evidence in the published scientific literature to permit conclusions concerning the use of salivary hormone testing for the diagnosis, treatment or monitoring of menopause and aging.
See Annotation Appendix E, "Non-FDA-Approved HT Treatment" in the original guideline document for more information.
Discuss Current Role of Hormone Therapy; Address Patient Concerns
The widespread publicity surrounding the Women's Health Initiative (WHI) has left many providers and many patients with the impression that the published results preclude any clinical role for HT. Discuss these concerns with patients and help put recent studies in the proper context. There are many serious reservations about the methodology and the meaning of the results of the WHI trial. Also, because of the heterogeneity found in the estrogen and progesterone receptors in humans, all population studies are difficult to project to the individual.
Clarify that, by and large, any conclusions which may be drawn from the WHI and related studies apply primarily to the relatively long-term use of HT for disease prevention rather than its short-term use for menopausal symptom relief.
Although hormone therapy did protect against osteoporosis-related fractures, cardiac protection could not be demonstrated in the WHI. The trial was halted because the observed benefits could not be shown to be as great as originally expected and did not outweigh the observed risks.
Consequently, although widely recommended up until relatively recently, in current clinical practice HT is now seldom initiated solely for the prevention of chronic disease.
Hormone therapy remains the most effective treatment for the relief of hot flashes, as well as urogenital and other menopausal symptoms. However, for many women, other non-hormone options may frequently provide adequate relief and should be considered.
In general, estrogen-only therapy (ET) may be less problematic than combination estrogen-progestin therapy (EPT), and transdermal estrogens (particularly in terms of the risk of venous thromboembolism) may not carry as much risk as oral estrogens. For a woman without a uterus, the short-term use of transdermal estrogen for menopausal symptom relief carries an extremely low risk. A more detailed discussion of these points follows throughout this guideline. (See Annotation #3, "Discuss HT Risks and Contraindications" for further details and specific references; also see Appendix C, "Provider Handout: HT Studies and Absolute and Relative Risks" in the original guideline document for an overview and risk table.)
Be aware that contraceptives, both pills (OCPs) and the transdermal patch, have much more potent estrogenic effects than HT, and that using or continuing OCPs or transdermal contraceptives in a perimenopausal woman cannot be considered in some way to be of less risk than initiating HT in the same woman.
A more detailed discussion of these points follows throughout this guideline. (See Appendix C, "Provider Handout: HT Studies and Absolute and Relative Risks" in the original guideline document for an overview and risk table.)
Ask about Alternative Therapies
A variety of herbal preparations and dietary supplements are marketed and used by patients as natural alternatives to HT. However, unless specifically asked, patients often do not volunteer information about their use.
These products may contain biologically active ingredients with significant physiologic effects. Their exact composition and consistency may be unknown or inconsistent. Very few products have been evaluated by well-controlled studies.
Patients will be well served and providers will gain credibility if factual information about alternative therapies is made available in a non-judgmental way. A strategy for guiding a discussion about the use, the known risks, and the potential benefits of several alternative therapies commonly used by menopausal women is included in Appendix E, "Non-FDA-Approved HT Treatments" in the original guideline document.
Counseling and Education Strategies
Women who actively participate in decision-making regarding their health care are more satisfied with their ultimate choices, especially if the approach is tailored to the woman's individual situation and reflects her priorities and values. The long-term commitment to HT, for women who choose this option, is in turn strengthened in those women who are more satisfied with their decision.
Presenting information in a variety of formats, including written materials, books, videos, Internet sites, and discussion groups is most effective in supporting the collaborative decision-making process and in maintaining a woman's commitment to HT.
Evidence supporting this recommendation is of classes: A, C, D, R
2a. Discuss Options for Menopausal Symptom Relief
Key Points:
- HT is the most effective treatment for hot flashes and other menopausal symptoms, although it is not always necessary and other options should be considered when appropriate.
- Not all sleep disorders among perimenopausal women are related to hormone changes; mood disorders or primary sleep disorders must also be considered.
- The association between hormone changes and the role of hormone therapy for memory and concentration, libido, mood, and many urinary symptoms is unclear.
Prior to menopause, often for several years, rising serum FSH levels and erratic ovarian follicle maturation lead to fluctuating and unpredictable estrogen and progesterone levels, accounting for many menopausal symptoms.
Most commonly, perimenopausal women experience menstrual irregularities, hot flashes, and vaginal dryness of varying degrees and severity. The sleep disruption from hot flashes may also lead to irritability, forgetfulness, and inability to concentrate. Fluctuating hormone levels are associated with emotional lability, but are not felt to be a direct cause of depression. Both disrupted sleep as well as urogenital changes can affect sexual functioning.
Hot Flashes and Night Sweats
Most women experience hot flashes (flushes) to some degree during the perimenopause. For many women, these symptoms are mild and of short duration, usually subsiding within five years, and do not require treatment beyond lifestyle adjustments, education, and reassurance.
For others, these symptoms may cause significant morbidity for many years and require additional treatment. Estrogen therapy is most effective, although various non-hormonal alternatives are sometimes helpful.
In particular, younger women who undergo oophorectomy will have a precipitous drop in estrogen levels, causing generally more severe and long-lasting hot flashes than women entering menopause spontaneously.
Characteristically, the hot flash involves an intermittent sensation of heat, flushing, and perspiration, usually limited to the head and upper torso. Some women report a prodrome of head pressure. The flushing is sometimes reported to be associated with palpitations and episodes of feeling faint. Hot flashes occurring during the night are commonly called night sweats.
Lifestyle modifications: Exercise, lighter clothing, sleeping in a cooler room, and reducing stress may be sufficient to manage hot flashes for many women. Avoidance of possible triggers, including spicy foods, caffeine, smoking, and alcohol may help.
Hormone therapy: The most effective means of relieving hot flashes is hormone therapy. Literature reviews indicate that hormone therapy will reduce the frequency of hot flashes by 80-90%. Therapy is usually limited to a few years, at most, and although the absolute risks are very low, they still must be fully discussed.
Selective estrogen receptor modulators (SERMs): SERMs are not indicated for menopausal symptom relief as they may actually worsen hot flashes.
Progestins: Megestrol and other progestins have been shown to reduce flushing. In patients with a history of breast or uterine cancer, megestrol decreased hot flashes by 80 percent.
Selective serotonin reuptake inhibitors (SSRIs): Venlafaxine (Effexor®), paroxetine (Paxil®), and fluoxetine (Prozac®) have been shown to be somewhat effective in relieving hot flashes. Perhaps two-thirds of women derive some benefit from these agents, compared to approximately one-third who may typically respond to placebo.
When effective, SSRIs in lower doses typically provide almost immediate relief from hot flashes, in distinction to the higher doses and much longer time frame needed to treat depression and other mood disorders. Consequently, a brief trial of a week or so may be sufficient to determine if an SSRI is going to be beneficial for hot flashes.
Other agents: There may be some benefit for relief of hot flashes shown with other agents including gabapentin (Neurontin®), clonidine (Catapres®), methyldopa (Aldomet®), and belladonna-phenobarbital-ergotamine preparations ([Bellergal® generics: Bellamine®] Bel-Pher-Ergot SR®), but various side effects limit their use.
See Appendix A, "Hormone Preparations" in the original guideline document for more information.
Phytoestrogens and isoflavones: Soy products or isoflavones, either through diet or supplementation, may not reduce the incidence of hot flashes. Inconsistencies among studies to date may be explained by different doses, products, sources, and processing. [Conclusion Grade III: See, Conclusion Grading Worksheet A - Annotation #2a (Soy Products) in the original guideline document]
Herbal preparations and dietary supplements: Black cohosh, dong quai, evening primrose oil, flaxseed, ginseng, progesterone creams, red clover, and wild yam extract are commonly used but poorly studied. See Appendix E, "Non-FDA Approved HT Treatments" in the original guideline document for more information about these agents.
Vaginal Dryness
Urogenital tissues are highly estrogen-sensitive. Vaginal dryness and vulvovaginal irritation are increasingly common following menopause. Atrophy and lack of lubrication may cause dyspareunia.
Hormone therapy: While nonprescription vaginal lubricants and moisturizers may provide some relief (e.g., Astroglide or Replens), estrogens are far superior. Local treatment of these symptoms with estrogen (via intravaginal ring, tablet, or cream) is preferred. With the exception of the fem ring, which gives systemic HT, there is little absorption with commonly used dosages and minimal risk of side effects or endometrial hyperplasia. Vaginal estrogens significantly reduce the rate of recurrent urinary tract infections compared to placebo.
See Annotation Appendix A, "Hormone Preparations" in the original guideline document for specific guidelines for various vaginal estrogen preparations and delivery systems.
Sleep Disturbances
Not all sleep disorders among menopausal women are related to hormonal changes; mood disorders or primary sleep disorders must also be considered. Among menopausal-related sleep disturbances, night sweats are frequently the underlying cause, but some women may experience sleep disturbances without hot flashes.
Older women who discontinue HT after many years of use may develop new-onset sleep disturbances. These may be their only complaints and may not be recognized as being related to HT cessation.
Lifestyle modifications: Avoiding exercise late in the day, taking a hot shower or bath immediately prior to going to bed and maintaining regular bedtimes can help improve sleep. Over-the-counter sleep aids can also be helpful.
Hormone therapy: Estrogen will often relieve and improve sleep by the alleviation of night sweats. In addition, women frequently report an improvement in sleep patterns with HT even if hot flashes or night sweats are not prominent features of their menopausal symptoms.
Mood and Anxiety Disturbances
There is a complex interplay between fluctuating hormone levels and mood. The connection between mood lability and anxiety on the one hand, and other menopausal symptoms, especially disturbed sleep, on the other, is also complicated. Social changes affecting menopausal women can also affect their mood and sense of well-being.
Women with a history of depression have a higher risk of menopausal mood disorders, but there is no direct association between menopause and depression. There is some evidence that estrogen may potentiate the effects of antidepressants, possibly by increasing or maintaining serotonin levels. Progestins may aggravate mood disturbances, perhaps negating any benefits of estrogen.
Lifestyle modifications: Adequate sleep, regular physical activity, and relaxation exercises may help with anxiety symptoms.
Hormone therapy: If there are other menopausal symptoms present, HT may be helpful. It is not shown if estrogen has a direct effect on mood, irritability, or anxiety. These effects may be due solely to the alleviation of hot flashes and sleep disturbances.
Selective serotonin reuptake inhibitors (SSRIs): The SSRIs are most helpful if the underlying problem is a primary mood disorder or depression rather than a manifestation of hot flashes or disturbed sleep.
Concentration Difficulties and Forgetfulness
Menopausal women often report difficulties with concentration and short-term memory. These symptoms are more likely related to hot flashes and impaired sleep. Although biologically plausible, a direct association of these symptoms with female hormone level remains unproven.
There is little, if any, evidence of any relationship between these mild, subjective symptoms and the later development of dementia. These are separate clinical entities and it is important to make this distinction clear when counseling patients. (Current concepts regarding dementia and HT are discussed in Annotation #2c, "Discuss Limited Role of HT for Disease Prevention" in the original guideline document.)
Lifestyle modifications: Exercise and sleep hygiene appear to be just as helpful for improving subjective cognitive symptoms as other alternatives.
Hormone therapy: Cognitive symptoms may improve simply by alleviating hot flashes or sleep disturbances; if HT has any direct effect, it is relatively minor.
Decreased Libido and Sexual Dysfunction
Night sweats, mood lability, vaginal dryness, and sleep disturbances may significantly affect sexual function and libido. In addition, menopausal women confront significant social changes regarding their own sense of well-being and the sexuality of their partners. Discussing relevant internal and external social issues the patient is experiencing is appropriate.
Hormone therapy: Besides relieving hot flashes and improving sleep, HT improves urogenital atrophy, thinning, dryness, and loss of elasticity, all which may cause dyspareunia. While this will improve sexual functioning for many women, HT has no proven direct effect on sexuality or libido.
Paradoxically, there is evidence that oral estrogens, particularly conjugated equine estrogens (CEE), may decrease free testosterone (by elevating sex hormone globulins) which may further decrease libido.
Selective serotonin reuptake inhibitors (SSRIs): Treating an underlying depression or mood disorder may help sexual dysfunction, although the SSRIs frequently cause anorgasmia or other sexual side effects.
Androgen supplementation: Particularly after surgical menopause, androgen supplementation has been shown to increase libido. Standard doses have not been established and existing testosterone assays are inadequate to provide guidance in either diagnosis or management. Moreover, supraphysiologic doses, with potentially serious side effects, are often quoted in the literature. All women must have careful counseling before starting these agents.
The position statement of the North American Menopause Society states in part that postmenopausal women with decreased sexual desire associated with personal distress may be candidates for androgen therapy. Recent studies have shown that transdermal testosterone in daily dosages in the range of 300 to 450 micrograms per deciliter had no serious side effects, and it improved low libido and sexual response when used over a period of three to six months. However, there is no medication approved by the Food and Drug Administration (FDA) for the management of any female sexual dysfunction, including the use of androgen supplementation. Testosterone treatment without concomitant estrogen therapy cannot be recommended because of a lack of evidence.
Adding androgen to standard HT regimens may provide some additional value for the prevention and treatment of osteoporosis, but the exact benefit must await further studies. Any risk, however slight, may not be justified if there is no benefit of therapy.
Urinary Incontinence and Urgency
Urinary urgency and irritation, more frequent urinary tract infections, urinary incontinence, and pelvic support problems are also more common following menopause. However, the relationship between urinary incontinence and menopause is not well understood. Estrogen was long thought helpful in the treatment of incontinence, but newer evidence suggests that it may actually exacerbate the problem. Most studies have shown little improvement in urinary stress incontinence, although urge incontinence may be more responsive to HT.
Headache
Among many other causes, headaches may be associated with fluctuating estrogen levels in perimenopause.
Hormone therapy may stabilize hormone levels and alleviate headache symptoms. Migraine headaches, per se, are not contraindications to HT.
HT may occasionally cause or aggravate headaches during either initiation or withdrawal; see Annotation #7, "Evaluate and Manage Side Effects" for guidelines for adjusting HT in these situations.
Other causes of headache and their treatment are discussed in the National Guideline Clearinghouse (NGC) summary of the Institute for Clinical Systems Improvement (ICSI) guideline Diagnosis and Treatment of Headache.
Evidence supporting this recommendation is of classes: A, C, D, M, R
2b. Discuss Options for Long-Term HT Users; Ensure Continued Bone Health
Key Points:
- Women who have recently discontinued hormone therapy are at risk for rapid bone loss; they must be monitored appropriately to ensure continued bone health.
- If HT is still indicated, consider whether a lower dose or different formulation might be more appropriate
Women who have recently discontinued HT are at risk for rapid bone loss. They must be identified and monitored appropriately to ensure continued bone health.
Until recently, women who had been on HT without any problems rarely considered changing their regimens. With the publication of the WHI data and in the face of continued concern about HT, many women have discontinued it on their own; some have done well and others have experienced a recurrence of hot flashes and other symptoms. In addition, some women may be reluctant to volunteer this information unless specifically asked.
Some women want advice about strategies for stopping HT while minimizing symptoms, others wish reassurance about continuing HT, and still others want information about different formulations or regimens that may be safer in some way.
While the absolute risks of continuing HT are very low, they cannot be dismissed entirely and must be addressed.
While many different formulations and regimens for hormone therapy have been suggested and are being used by many practitioners, there is very little firm data to support these recommendations. However, there is some emerging data suggesting that transdermal estrogens may be less likely to increase the risk of venous thromboembolism (VTE) than oral estrogens, particularly CEE/medroxyprogesterone acetate (MPA).
Regularly evaluate each woman's need for hormone therapy.
- Consider the original indication for HT and whether it still remains.
- Check for the development of any medical conditions, particularly coronary heart disease (CHD), which might mandate greater caution.
- If HT is still indicated, consider whether a lower dose or different formulation might be more appropriate.
See Annotations 6b, "Guidelines for Modifying HT in Long-Term Users" and 6c, "Guidelines for Discontinuing HT in Long-Term Users" for guidelines for modifying hormone therapy regimens.
2c. Discuss Limited Role of HT for Disease Prevention
Key Points:
- Long-term hormone therapy is rarely initiated for the prevention of chronic disease.
- Recent data has called into question the long-held belief that HT protects against the development of CHD.
- HT protects against the development of osteoporosis and hip and vertebral fractures; several other agents are equally effective.
While HT has recently been proven to prevent osteoporotic fractures and lower the risk of colon cancer, current practice largely limits its role to the treatment of menopausal symptoms.
HT is seldom initiated solely for long-term disease prevention. However, in light of the uncertainty about the role of HT, current concepts regarding its relationship to several chronic conditions are summarized below.
Osteoporosis: Prevention of osteoporosis had been the most well-documented and widely accepted use of HT. While observational studies had indicated that HT provided protection against hip and vertebral fractures, the WHI was the first randomized trial to confirm this finding.
The benefits of HT are maintained as long as it is continued, but bone loss resumes when treatment is stopped, and any residual benefit is rapidly lost. Bone mineral density should be measured when women discontinue HT after several years of use.
See the NGC summary of the ICSI guideline
Diagnosis and Treatment of Osteoporosis for specific recommendations regarding bone mineral density (BMD) testing and osteoporosis treatment.
In summary, several other agents are as effective as hormone therapy in preventing fracture due to osteoporosis; these include:
Bisphosphonates: Alendronate (Fosamax®), risedronate (Actonel®, and ibandronate (Boniva®) are commonly used for both prevention and treatment of osteoporosis. Their use may be complicated by esophageal irritation, but proper dosing minimizes this problem. Bisphosphonates in combination with estrogen are more effective than either agent alone.
Selective estrogen receptor modulators (SERMs): SERMs (e.g., raloxifene [Evista®] are indicated for the prevention and treatment of osteoporosis. They are not indicated for the treatment of menopausal symptoms and may even aggravate hot flashes in some women. They also do not help vaginal atrophy. As with estrogen, a past history of venous thrombosis is a contraindication to their use. Current venous thrombosis is an absolute contraindication.
Calcitonin (Miacalcin®): The nasal spray used for osteoporosis treatment that inhibits bone resorption and reduces fracture rates. Nasal irritation and cost limit its use.
Parathyroid hormone (PTH e.g., teriparatide [Forteo®]): Daily subcutaneous injections are used for osteoporosis treatment. PTH is Food and Drug Administration (FDA) approved but carries a black box warning about possible risk for osteosarcoma based on rat studies.
Coronary Heart Disease (CHD)
Many observational studies and known biologic effects suggested a beneficial effect of estrogen for CHD prevention. However, more recent prospective randomized controlled trials (WHI, others) have not shown any benefit of HT for either primary or secondary prevention and have suggested that HT may even cause myocardial infarction.
These discrepancies continue to be hotly debated. The observational studies may have been affected by selection bias, in that healthier women with better access to health care are more likely to use HT. Alternatively, the prospective trials may have been confounded by the inclusion of older women with pre-existing CHD. There are also experimental data from nonhuman primates which could explain these discrepancies. Further randomized trials of early initiation of HT in women as they enter menopause may also help explain these paradoxes. While estrogen given in early menopause may prevent atherosclerosis, later estrogen use, after lesions develop, may actually precipitate coronary events.
Progestins may also account for the deleterious effects of HT. However, there is no specific evidence that estrogen alone is safer or more beneficial.
Specific recommendations from several sources currently include the following:
- Identify and treat all CHD risk factors.
- Do not initiate HT for the prevention of CHD.
- Do not initiate HT in patients with known CHD.
- If CHD develops while on HT, consider other alternatives.
Alzheimer's disease (AD): Some studies have indicated that HT may improve cognitive functioning in perimenopausal women, but this may be due solely to the alleviation of menopausal symptoms. It is unknown whether long-term HT has any benefit for the prevention or progression of dementia, including AD. More recent studies have reported an increased risk of dementia among older women taking HT.
Again, these discrepancies may be explained by selection bias, by the inclusion of older women who were past a "window" in early menopause when HT would have been helpful, or by other factors. Additionally, there are studies on the cellular level that demonstrate neuroprotective effects of estrogen. These findings have significance in that there are demonstrated improvements in balance and reflexes in estrogen users. As with the controversy surrounding CHD, the exact relationship between AD and HT is uncertain and may remain so for quite some time.
Colorectal cancer: The WHI estrogen-progestin (EPT) arm confirmed that HT lowers the risk of developing colon cancer. The estrogen-only arm did not show a reduction in colon cancer. However, HT should not be used solely for colon cancer prevention and women taking HT still need colorectal cancer screening at the recommended intervals.
Skin/Wound healing: HT has beneficial effects on collagen metabolism, improving skin tone and wound healing, but it should not be initiated solely for that purpose.
Tooth loss: HT reduces maxillary and mandibular osteoporosis and prevents resulting tooth loss, but it should not be initiated solely for that purpose.
Macular degeneration: HT reduces the risk of developing age-related macular degeneration, but it should not be initiated solely for that purpose.
Evidence supporting this recommendation is of classes: A, B, C, M, R, X
- Discuss HT Risks and Contraindications
Key Points:
- There may be a small increase in breast cancer risk after several years of HT, although this continues to be debated.
- Progestins added to the HT regimen largely eliminate any increased risk of endometrial cancer.
- The risk for venous thromboembolism (VTE) is increased approximately twofold in current, but not former, users of HT, although the absolute risk is still very low.
Breast Cancer
The possible increased risk of breast cancer with HT is a primary concern of many women. Many investigators, including those associated with the WHI, have indeed reported a relationship between HT and the development of breast cancer. Others view any apparent increase as statistically insignificant or even spurious.
There may be a small increase in breast cancer risk after several years of hormone therapy. Women who take HT for less than 3 years (e.g., for menopausal symptom relief) may not be at any increased risk. If real, the absolute risk after three to five years is small, on the order of approximately one additional breast cancer per 1,000 women per year.
In the estrogen only arm of WHI, there was no increased risk of breast cancer. The relative risk was 0.77 (0.59 to 1.01), a trend toward decreased risk.
Earlier studies seemed to indicate that breast cancer mortality did not seem to be increased with hormone therapy, and the breast cancers arising in women on HT tended to be less advanced and to have more favorable prognoses. More recent studies have reported a trend toward increased tumor size, lymph node involvement, and stage at time of diagnosis, in HT users. These studies also demonstrated an increased frequency of abnormal mammograms among HT users.
In summary, more prolonged use of HT may increase the risk of developing breast cancer, or it may simply stimulate the growth of preexisting breast cancers, or there may be other explanations for the observed data. Whatever the case, this possible increased risk cannot be dismissed and the limitations of current knowledge must be discussed. As with other potential risks of HT, there is no evidence that different formulations or lower doses of estrogens are necessarily of any lesser risk than those more widely used or studied.
Endometrial cancer: The risk of developing endometrial cancer is increased only in women taking unopposed estrogen (without progestin). Any additional risk is eliminated when progestogen is added to the HT regimen.
Unopposed estrogen results in a significant increase in the risk of endometrial hyperplasia after only one to three years. Endometrial hyperplasia may eventually lead to atypical hyperplasia and even malignancy if unopposed estrogen is continued.
Gallbladder disease: Observational studies, as well as more recent prospective trials, suggest that the risk of gallbladder disease (cholelithiasis, cholecystitis) and cholecystectomy is increased in women taking HT. This effect was seen in women taking estrogen only as well as estrogen/progestin combination therapy.
Venous thromboembolism (VTE): The risk for VTE appears to be increased approximately twofold in current, but not former users of HT. The absolute risk is still relatively low, being increased from approximately 15 cases per 10,000 women in the general population to approximately 30 cases per 10,000 women on HT. Transdermal estrogens do not seem to carry the increased risk of VTE seen with oral estrogens. In experimental studies, the deleterious effects of oral estrogens on several different clotting parameters, including APC sensitivity, protein C, and fibrinolysis, were not seen with transdermal estrogens.
Be aware that transdermal contraceptives have much more potent estrogenic effects than the transdermal formulations used for hormone therapy and cannot be similarly considered to be of less risk than oral estrogens.
Myocardial infarction (MI): There does not appear to be an overall effect on the rate of fatal MI associated with an HT regimen, although the EPT arm of the WHI trial noted an increase in the rate of nonfatal MI. The estrogen-only arm did not show an increase in MI.
Alzheimer's disease: There are discrepancies in the evidence that estrogen has any specific effects on cognitive performance. The Women's Health Initiative Memory Study (WHIMS) indicated that hormone therapy adversely affects global cognition, which includes memory and other basic mental abilities including concentration, language, and abstract reasoning. In particular, EPT doubled the risk of dementia in older women. In the ET group, there was a weaker, but similar trend in the results.
Ovarian cancer: There may be a weak association between the prolonged use of estrogen and ovarian cancer, but no epidemiological evidence has been established.
Contraindications to HT
Unexplained vaginal bleeding and pregnancy: These are temporary but absolute contraindications to HT.
Past history of breast cancer or endometrial cancer: While usually considered contraindications to HT, short-term use for severe menopausal symptoms may be considered with proper precautions.
An increasing number of younger women are being cured of breast cancer, and some of these women may require treatment for severe vasomotor symptoms or significant vaginal atrophy. Short-term oral or transdermal HT or intravaginal estrogen may be considered after consultation with an oncologist.
Most oncologists agree that women with past history of stage I endometrial cancer that has been successfully treated may safely use HT if it is otherwise indicated.
Women with a past history of venous thrombosis are at increased risk for recurrence; however, taking OCPs or HT confers an overall low increase to this risk of recurrence.
Family history of premenopausal breast cancer: In the Iowa Women's Health Study there was not an increased incidence of breast cancer in HT users with a family history of breast cancer, relative to those HT users without a family history of cancer.
Hypertriglyceridemia: Oral estrogens are contraindicated because of the danger of precipitating pancreatitis. Transdermal estrogens or intravaginal estrogens, which avoid the first-pass hepatic effect, do not carry this risk.
Chronic liver disease: Oral HT is a relative contraindication. Again, transdermal and intravaginal estrogen avoid the first-pass hepatic effect of oral HT.
HT is not contraindicated in these clinical settings where many practitioners have often been reluctant (often unjustifiably so) to recommend oral contraceptives; OCPs have much more potent estrogenic effects than HT. These conditions include:
- Endometriosis
- Fibrocystic breast changes
- Hypertension
- Mastalgia
- Migraine headaches
- Obesity
- Tobacco use
- Uterine leiomyomata (fibroids)
Evidence supporting this recommendation is of classes: A, B, C, M, R
- Collaborative Decision-Making: Clarify Patient's Values and Priorities
Key Points:
- Careful consideration and in-depth discussion are required whenever the initiation or continuation of hormone therapy is considered.
- Address the discrepancies and gaps in our knowledge and address any factual misunderstandings.
- Help each woman clarify her individual values and priorities so that she may decide how important each of the potential benefits and risks of HT is to her unique situation.
Truly collaborative decision-making requires that each woman clarify her individual values and priorities, with help from her provider if she wishes, so that she may decide how important each of the potential benefits and risks of HT is to her unique situation.
Inquire about each woman's particular goals and concerns about menopause and her attitudes toward taking medications in general and hormone therapy in particular.
Clarify the distinction between long-term HT for preventive therapy and its short-term use for symptom relief.
Discrepancies among the various studies continue to be debated, and it is unlikely that definitive information or consensus will be available anytime soon. Acknowledge this uncertainty and take the necessary time for an in-depth discussion with women who are considering either starting or continuing hormone therapy. It is often helpful to discuss the patient's understanding and perception of the risks of HT and of various conditions and to help put them in perspective.
Many women consider any possible increased risk of breast cancer to outweigh any possible benefit of HT.
Many women find the prospect of the resumption or continuation of their menses to be unacceptable, or consider irregular spotting to be too worrisome to justify HT use.
Some women consider any use of HT to represent the unnecessary medicalization of menopause. Others may value alternative therapies for menopausal symptoms more highly than traditional medical practices. Some women object to conjugated equine estrogens because of animal cruelty concerns.
Misunderstandings about hormone therapy are not infrequent; help women address these and other concerns.
- Many women believe that they must always take estrogen if they once start, or that their menses will continue indefinitely on HT
- Many women believe that use of hormone therapy merely postpones the occurrence of menopausal symptoms to a later date
- Many women overestimate their baseline risk of breast cancer
Individual women, even if they have identical clinical situations, will often arrive at completely different decisions regarding hormone therapy. As long as the decision is right for each individual patient, it is the appropriate choice.
There is no best or easy approach to this step of the decision-making process. Patience, insight, and care are required to recognize different perspectives and to achieve a respectful and balanced discussion about HT and midlife women's health.
6a. Guidelines for Initiating HT
Key Points:
- There is no firm evidence that any one form of estrogen or progestin is superior to another, although different preparations are useful in different clinical settings.
- Progestins are not necessary in women who have had a hysterectomy.
Jointly decide on the hormone therapy regimen best suited to each woman's particular characteristics and needs.
There is no firm evidence that any one form of estrogen or progestin is superior to another. On the other hand, transdermal estrogens do not show the same deleterious effects on clotting parameters as oral estrogens.
Estrogen-Progestin (EPT-Combined) vs. Estrogen-Only (ET) Hormone Therapy
Progestins are combined with estrogen to prevent endometrial hyperplasia and to minimize the risk of endometrial cancer in women with an intact uterus.
Progestins are not necessary in women who have had a hysterectomy.
Progestins are also not necessary in women receiving intravaginal estrogens; the systemic absorption is insufficient to cause endometrial hyperplasia even if they have an intact uterus.
Please refer to Appendix A, "Hormone Preparations, Table IV: Estrogen-Progestin Preparations" in the original guideline document for information on delivery mode and dosage.
Cyclic vs. Continuous Combined Hormone Therapy
The terms cyclic and continuous refer only to the progestogen component of combined HT.
Oral estrogen should always be given every day; there is no advantage to the once popular intermittent dosing as it may cause increased hot flashes or migraines during the time that estrogen is withheld.
Progestins may be given either cyclically (generally in the earlier years of perimenopause) or continuously (generally later in menopause) as detailed below.
European evidence suggests that continuous progestin/estrogen use may reduce by 80% the risk of endometrial cancer compared with five or more years of cyclic estrogen/progesterone which showed a 60% increase in risk of endometrial cancer over no treatment. Because different HT agents are used in Europe, the applicability of this finding to U.S. medical practice has been questioned.
For information on delivery mode and dosage of combination estrogen-progestin preparations, estrogen preparations and progesterone/progestin preparations, see Appendix A, "Hormone Preparations," in the original guideline document.
Discuss Expected Bleeding Patterns
Younger women with occasional menses may still be having intermittent ovarian activity. Initiating HT with a cyclic progestin regimen minimizes irregular bleeding and spotting and usually results in a predictable monthly withdrawal bleed. Some women may achieve eventual amenorrhea, although it may require several months or longer.
Older women who have been on cyclic therapy for two to three years may be switched to continuous combined HT. If they have been amenorrheic on cyclic HT, they are likely to remain so on combination HT. However, even if they have been having light withdrawal bleeding, they may still become amenorrheic on combined HT.
Theoretically, menopausal women who have been amenorrheic for some time could be started directly on combination therapy, but as a practical matter, HT is rarely initiated in these women.
Continuous oral progestin may cause unpredictable vaginal bleeding, with or without spotting, for many months. Five to 20% of these women may never achieve amenorrhea and may opt for cyclic hormone therapy to achieve a more predictable bleeding pattern.
Discuss Possible Side Effects
Estrogenic side effects: Mastalgia, fluid retention, nausea, leg cramps, and aggravation of headaches are all side effects to estrogen therapy. Rarely, estrogen may cause an unexpected rise in blood pressure.
Reassure women with mastalgia that it is not in any way associated with an increased risk of breast cancer.
Progestin side effects: Fluid retention and bloating, headache, mastalgia, oily skin and acne, mood alterations, and premenstrual-type symptoms are possible side effects.
Although studies using progestins versus progesterone in HT have shown similar side effect profiles, some patients may have fewer side effects or less severe side effects with progesterone preparations.
Refer to Annotation #7, "Evaluate and Manage Side Effects," for further details and specific management guidelines.
Prescribing hormone therapy: There is no firm evidence that any particular form or dose of oral estrogen or progestin is superior to another. On the other hand, transdermal estrogens do not carry the same increased risk of VTE seen with oral estrogens.
Although there is not evidence from randomized, controlled trials, several authorities make the reasonable recommendation to use the lowest possible dose for the shortest possible time (e.g. American College of Obstetricians and Gynecologists [ACOG], NIHMS, and National Institute of Health [NIH]).
Hormone therapy for hot flashes: Doses as low as 0.025 milligrams (mg) of transdermal estradiol, 0.5 mg of oral estradiol, or 0.3 mg of CEE may be effective.
Following surgical menopause, some women may require as much as 2.5 mg CEE or 2 mg estradiol daily for effective symptom relief.
Hormone therapy for urogenital symptoms: If needed for urogenital symptoms only, consider intravaginal estrogens in the form of cream, gel, ring, or tablet.
Systemic estrogens (either oral or transdermal) may be required to have an effect on urinary epithelium for alleviation of frequency, urgency, or incontinence.
Women Who May Still Need Contraception
Younger perimenopausal women with irregular menses and hot flashes may still be occasionally ovulating. Consider low-dose OCPs rather than HT to control symptoms and minimize irregular bleeding while providing still-needed contraception. OCPs are contraindicated in women age 35 who smoke. Prescribe low-estrogen OCPs to minimize any risk of thromboembolic events.
Be aware that contraceptives, pills (OCPs), patch, and ring have much more potent estrogenic effects than HT, and that using or continuing OCPs or transdermal contraceptives in a perimenopausal woman should not be considered in some way to be of less risk than initiating HT in the same woman.
Testing may be most useful for the older woman (over age 50) still on OCPs who is interested in confirming that OCPs can be discontinued. FSH levels can fluctuate during the early perimenopause; therefore, an isolated FSH level, particularly if only borderline elevated, is not totally confirmatory. Alternatively, although estradiol levels can occasionally remain elevated after discontinuation of OCPs, a low estradiol level is a reliable confirmation of menopause.
Evidence supporting this recommendation is of classes: A, C, M
6b. Guidelines for Modifying Hormone Therapy in Long-Term Users
Key Points:
- Many women may require continued HT for adequate menopausal symptom relief, although older women may be able to decrease their dose without precipitating the resumption of hot flashes.
- While not proven, it seems prudent to use transdermal estrogen, in the lowest effective dose, when possible
- There is very little evidence supporting the use of unopposed estrogen (as a strategy to eliminate possible progestin-related risks), even with careful endometrial surveillance. However, for individual women, this may be the only effective alternative for intolerable hot flashes.
Many women may require continued hormone therapy for adequate menopausal symptom relief; they must be fully informed of the risks and benefits and have regular follow up.
There is very limited data to suggest that different formulations or dosing regimens are significantly safer than those which have been better studied or more widely used (CEE/MPA). Nonetheless, it seems prudent to use transdermal estrogen, in the lowest effective dose, when possible. Many older women may be able to decrease their dose of estrogen without precipitating the resumption of hot flashes.
There is good evidence that lower doses of estrogen (CEE 0.3 mg daily, estradiol 0.5 mg daily, 0.025-0.05 mg transdermal estradiol) maintain bone density nearly as well as higher doses. Continue to monitor bone density in the first year after decreasing the estrogen dose.
Transdermal estrogen has a better side effect profile and a lower risk of VTE than oral estrogens.
Although progestins may be responsible for an increased breast cancer risk in long-term users of combination EPT, there is little, if any, evidence to support using "long cycle" progestin dosing (12 to 14 days of progestin every 3 to 6 months) or the progestin secreting intrauterine device (IUD) as a risk reducing strategy. Furthermore, there is no evidence at all to support using of unopposed estrogen, even in low doses and with careful endometrial surveillance, for this purpose. (These may, however, be among the only reasonable alternatives for women who cannot tolerate progestins and have intolerable hot flashes that are not relieved by non-hormonal medications. See Annotation #7, "Evaluate and Manage Side Effects," for further information.)
Evidence supporting this recommendation is of classes: C, D
6c. Guidelines for Discontinuing HT in Long-Term Users
Key Points:
- There is very little firm data to support these recommendations or guide practitioners for discontinuing hormone therapy in long-term users.
- Women may undergo rapid bone loss upon stopping; bone health, specifically bone density, must be considered and carefully monitored.
Many regimens have been suggested and are being used by many practitioners for discontinuing hormone therapy in long-term users, but there is very little firm data to support these recommendations or guide this process.
Many women do not notice any symptoms even with abrupt cessation of HT, while others may experience a recurrence of hot flashes. In older menopausal women, sleep disorders, rather than hot flashes, may be the major manifestation of renewed menopausal symptoms.
There is some biologic basis for recommending tapering hormone therapy over several months rather than stopping abruptly. As the washout period of CEE is longer than with other forms of estrogen, switching to a different formulation, such as estradiol, may also be helpful.
Consider alternative therapies for menopausal symptom relief, as outlined in Section 2a, while tapering HT.
As noted before, no matter how long a woman has been on HT, she may undergo rapid bone loss upon stopping. Bone health, specifically bone density, must be considered and carefully monitored.
Evidence supporting this recommendation is of class: R
- Evaluate and Manage Side Effects
Key Points:
- Irregular bleeding usually resolves within 6 to 12 months following initiation of HT; try to avoid changing regimens too quickly.
- Bleeding occurring after 12 months of amenorrhea should be considered as an episode of postmenopausal bleeding and appropriately evaluated.
- Any bleeding pattern which is of concern, based on the clinical judgment of the provider, should be appropriately evaluated.
The decision to take HT is often reached after considerable soul-searching by the patient. Her continued use of HT will likely be further dependent on the nature and resolution of any significant side effects that occur.
Bleeding
Irregular bleeding following the initiation of HT is very common. Advising the patient of this before initiating therapy may strengthen adherence. See "Discuss Expected Bleeding Patterns" in Annotation #6a, "Guidelines for Initiating HT" for a summary of expected patterns of continued or irregular bleeding.
For most women, irregular bleeding improves within approximately 6 to 12 months of initiating HT; changing HT regimens or formulations too quickly is unlikely to be helpful.
Evaluation of "Abnormal" Bleeding
There are no universally accepted criteria for defining "abnormal" bleeding and mandating further evaluation. Most bleeding is due to benign causes; early stage endometrial cancer is virtually always curable, so it is important to detect early.
The guideline developers believe the following criteria are reasonably cautious but minimize unnecessary endometrial biopsies.
For women on cyclic HT: Cyclic withdrawal bleeding is to be expected. Evaluate any unusually prolonged or heavy bleeding occurring near the end of the progestogen phase of the cycle, or breakthrough bleeding occurring at any other time.
For women on continuous HT: Irregular bleeding may often persist for 6 to 12 months; evaluate any bleeding that persists any longer than this or that occurs after amenorrhea has become established.
There are various modalities used to evaluate abnormal bleeding, including endometrial sampling (biopsy or dilation and curettage [D & C]), endovaginal ultrasound (EVUS), sonohysterography, and hysteroscopy.
Given the strengths and limitations of both EVUS and endometrial biopsy, many experts advocate combining the two tests. Other tests, such as D&C, hysteroscopy, and saline intrauterine infusion during EVUS, are better reserved for cases where EVUS and endometrial biopsy results are equivocal.
Finally, in the asymptomatic HT patient found to have a thickened endometrium by EVUS evaluation and subsequent negative findings at endometrial biopsy, at least one study shows additional sampling is not warranted.
Endometrial sampling (biopsy and D&C): The historical "gold standard" for histologic evaluation of the endometrium has been dilation and curettage (D&C), yet this surgical procedure has a known false negative rate of 2 to 6%. Furthermore, D&C requires an operating room setting with attendant risks of anesthesia, hemorrhage, infection, and uterine perforation. Finally, cost considerations make the procedure impractical for first-line evaluation of endometrial thickness.
In response to this problem, several collection devices to allow for endometrial sampling (endometrial biopsy) in an outpatient setting have been created. However, these devices have a greater false negative percentage than D&C, and can be successfully employed in only about 70 to 80% of postmenopausal women.
Endovaginal Ultrasound (EVUS): Endovaginal ultrasonographic (EVUS), alone or in conjunction with endometrial sampling, has been advocated as a safe and cost-effective method for evaluating a patient on HT for endometrial hyperplasia.
A positive correlation between an increase in endometrial thickness detected on EVUS and endometrial pathology, ranging from endometrial polyps to endometrial hyperplasia to endometrial carcinoma, has been demonstrated.
Sonohysterography: Sonohysterography is performed by instilling 10 cc of sterile saline into the uterine cavity via a flexible catheter. This technique separates the two walls of the endometrium and produces a sonolucent window through which endometrial thickness can be completely examined.
Sonohysterography can detect focal areas of endometrial thickening, which suggests a true pathologic condition is present. In particular, sonohysterography is useful in delineating polyps and submucous fibroids. Endometrial sampling via directed endometrial biopsy, D & C, or operative hysteroscopy is needed to complete the evaluation under these circumstances.
Hysteroscopy: Hysteroscopy involves the use of a fiberoptic viewing scope and a distending medium to directly view the endometrial cavity. There are a wide variety of such devices and media. Some hysteroscopes have been designed for use in an office setting with minimal or no anesthesia or sedation, using carbon dioxide as a distending medium.
The ability to directly visualize potentially pathologic tissue has led many in the field to now define hysteroscopy as the "gold standard." However, major disadvantages to this procedure include the cost, operator learning curve, and the difficulty to use hysteroscopy in the face of cervical stenosis or active uterine bleeding.
Management of Bleeding Occurring while on Cyclic HT
Most often, irregular bleeding occurring after the initiation of cyclic HT will resolve within a few months, when ovarian function ceases completely.
If intervention becomes necessary, increase the progestogen dose, if tolerated. If endometrial biopsy is performed, persistent proliferative activity during the progestogen phase gives further weight to this approach.
If HT is initiated in a woman who has been amenorrheic for many years, continuous therapy is preferred as cyclic HT may lead to a resumption of menses/bleeding.
Management of Bleeding Occurring while on Continuous HT
Some women may have irregular spotting and bleeding for many months after initiating continuous HT. Many of these women may end up switching back to cyclic HT, so that their bleeding patterns are at least predictable.
Persistent bleeding while on continuous HT is usually due to an unstable atrophic endometrium. It may resolve with an increased progestogen dose or with the use of a levonorgestrel-secreting IUD.
Weight Gain
Around menopause, most women gain weight and experience an increase in their proportion of central abdominal fat. Contrary to various widely-held beliefs, this is neither caused nor alleviated by hormone therapy.
Some women experience breast tenderness and fluid retention shortly after initiating HT and these symptoms may contribute to a subjective sense of weight gain; they will usually resolve after a few months.
Patient education that anticipates concerns about weight gain may be helpful. Weighing patients at each visit may help reassure them that although their body fat distribution may change, actual weight over time is relatively stable.
Management of Headache
As discussed in more detail in Annotation #2a, "Discuss Options for Menopausal Symptom Relief," estrogen therapy may occasionally aggravate migraine headaches. Switching to a lower dose or from oral to transdermal estrogen (with more even absorption) may be helpful.
Management of Estrogenic Side Effects
Common estrogenic side effects are listed in Annotation #6a, "Guidelines for Initiating HT."
Fluid retention and headache may be related to either estrogen or progestins; modifying the progestogen first is usually the better strategy (see below).
Breast tenderness is more likely to be alleviated with lower estrogen dosages, although adjusting the progestogen may occasionally be effective if the symptoms seem to have a cyclic quality (see below).
Switching to the transdermal estrogen preparations may alleviate nausea.
Management of Progestogenic Side Effects
Common progestogenic side effects are listed in Annotation #6a, "Guidelines for Initiating HT."
Fluid retention and headache are most likely related to progestins. However, if a different formulation of progestogen is not helpful, consider modifying the estrogen component (see above).
Although MPA has been among the most widely used progestins, other agents, especially micronized progesterone (Prometrium) may be better tolerated.
Continuous HT, with more constant systemic absorption than cyclic HT, may be tried for the relief of mastalgia, headaches, and premenstrual-type symptoms if adjusting the two components individually is not effective.
The levonorgestrel-secreting IUD and vaginal progesterone suppositories keep systemic absorption to an absolute minimum and provide adequate endometrial protection for women on low-dose estrogen.
Using cyclic progestins for a full 12 to 14 days but only every 3 to 6 months also minimizes side effects. This regimen may also provide adequate endometrial protection, but the studies are small and the data is limited.
Ultimately, for a few women who cannot tolerate progestins at all, unopposed low-dose estrogen may be the only reasonable alternative for severe hot flashes unrelieved by non-hormonal medications. In this situation, informed consent, careful clinical judgment, and regular endometrial surveillance are essential.
Evidence supporting this recommendation is of classes: A, C, D, M, R
- Follow-Up
Key Points:
- Provide support and encouragement, through accessibility and close follow-up, for women who have recently initiated hormone therapy.
- Regularly evaluate each woman's ongoing need for hormone therapy.
- Be aware of changes in understanding and in standards of care associated with hormone therapy.
Up to one-third of women will need to modify or change their hormone therapy regimen if they are to be successful in its use. Consequently, follow-up and stay in contact within the first few months after initiating hormonal therapy. Research has shown that a significant number of patients never even fill their prescriptions or discontinue hormone therapy, often without their provider's knowledge.
For women on a stable HT regimen, reassess their need for continuing therapy on a regular basis:
- Consider the original indication for HT and whether it is still valid.
- Check for the development of any medical conditions, particularly CHD, that might mandate greater caution.
- Consider whether a lower dose or different formulation might be more appropriate.
For women who may have stopped HT since their last encounter, consider bone mineral density measurement. (See also Annotation #6c, "Guidelines for Discontinuing HT in Long-term Users," for additional information on this topic.)
The knowledge and understanding of the role of hormone therapy, as well as the standards of care associated with its use, are frequently changing. The provider should be aware of any new clinical studies such as KEEPS (Kronos Early Estrogen Prevention Study) due to be completed in 2010 or practice guidelines that become available, in order to best serve the needs of patients.
Definitions:
Conclusion Grades:
Grade I: The evidence consists of results from studies of strong design for answering the question addressed. The results are both clinically important and consistent with minor exceptions at most. The results are free of any significant doubts about generalizability, bias, and flaws in research design. Studies with negative results have sufficiently large samples to have adequate statistical power.
Grade II: The evidence consists of results from studies of strong design for answering the question addressed, but there is some uncertainty attached to the conclusion because of inconsistencies among the results from the studies or because of minor doubts about generalizability, bias, research design flaws, or adequacy of sample size. Alternatively, the evidence consists solely of results from weaker designs for the question addressed, but the results have been confirmed in separate studies and are consistent with minor exceptions at most.
Grade III: The evidence consists of results from studies of strong design for answering the question addressed, but there is substantial uncertainty attached to the conclusion because of inconsistencies among the results of different studies or because of serious doubts about generalizability, bias, research design flaws, or adequacy of sample size. Alternatively, the evidence consists solely of results from a limited number of studies of weak design for answering the question addressed.
Grade Not Assignable: There is no evidence available that directly supports or refutes the conclusion.
Classes of Research Reports:
- Primary Reports of New Data Collection:
Class A:
- Randomized, controlled trial
Class B:
Class C:
- Non-randomized trial with concurrent or historical controls
- Case-control study
- Study of sensitivity and specificity of a diagnostic test
- Population-based descriptive study
Class D:
- Cross-sectional study
- Case series
- Case report
- Reports that Synthesize or Reflect upon Collections of Primary Reports:
Class M:
- Meta-analysis
- Systematic review
- Decision analysis
- Cost-effectiveness analysis
Class R:
- Consensus statement
- Consensus report
- Narrative review
Class X:
