Menopause and Hormonal Therapy Steven Wilson, M.D. Epidemiology: The average age at menopause is 51 years, with about 5% of women experiencing premature menopause before the age 40. Menopause occurs The mean age of menopause is 51; it occurs before age 40 in 5% of women earlier in women who live at high altitudes and women who smoke. About 15% of women go through surgical menopause. The average length of menopause is Average length of perimenopause 4 years 4 years so this is a long process and unfortunately it is difficult to predict in an Earlier menopause is seen in cigarette smokers, those living at higher altitude individual woman how long it will take to get through menopause. Generally, women will experience a shortening of the intermenstrual interval then Physiology: lengthening, then has cessation of menopause, and then they have waxing and waning periods through this period of time. Symptoms of estrogen lack occur Premenopausal women after age 40 often have shorter cycles which lengthen just prior to the cessation of periods as well. before menopause. The physiology of menopause is that of increasing ovarian resistance to FSH, declining estrogen levels and increasing FSH levels. The classic symptom of Physiology of menopause menopause is the hot flash. Hot flashes are very common in menopause. Most women, but not all women, will experience vasomotor instability. It tends to be - increased ovarian resistance to FSH less severe in obese women likely because they have higher circulating estrogen levels. It is associated with peripheral vasodilatation. - increased FSH levels (diagnostic level > 40) Other symptoms of menopause include urogenital atrophy and decreased - decreased estrogen vaginal lubrication manifested as painful intercourse. Some women may also experience urinary frequency or urgency. They may experience urinary tract infections with increased frequency and they may experience urinary - estrone (less potent than estradiol) is the major circulating estrogen incontinence. There is no increased risk of major depression in menopause but many women do experience other symptoms. There can certainly be insomnia Symptoms: associated with nocturnal hot flashes that interrupt sleep and there appears to be a decrease in short-term memory in women who are going through menopause Vasomotor instability - "hot flashes" and women who are post-menopausal. - affect 80% of women Management of the symptoms of menopause, it is clear that estrogen is the most effective therapy for the treatment of the hot flashes and vaginal atrophy - less severe in obese women of menopause. Provera is an option of progesterone that is in general an option for women who are intolerant of estrogen or in whom estrogen is contraindicated. Clonidine orally or as a transdermal patch is less effective than Urogenital atrophy estrogen, but better than placebo and can be used in normotensive women follow up of blood pressure and symptoms to be sure that it is tolerated. - decreased lubrication - dyspareunia Not listed on the slide are phytoestrogens which are available in plant sources. - UTIs Soy is particularly one that women may be using. There is relatively little data to guide us however in terms of dosing and benefits and actual regimen to Mood disorders prescribe. Suggesting decreased alcohol, caffeine and spicy food intake may be of benefit. - no increase in major depression, ?mild symptoms of depression may Hormonal therapy and prevention. The preventive benefits with respect to sometimes occur. hormone therapy are many. The strongest evidence to date exists for preventive benefits with respect to coronary heart disease and osteoporosis, there is some - hot flashes may interfere with sleep important evidence that using hormonal therapy decreases mortality. There is less robust evidence with respect to benefits in stroke and colon cancer risk. Treatment of symptoms: There is a growing body of evidence with respect to cognitive function delay - estrogen 95 % effective and onset in Alzheimer's disease. Women who are on estrogen lose fewer teeth than women who are not on estrogen and there may be some cosmetic benefits with respect to skin appearance as well. - progesterone 10 mg qd 85% effective With respect to hormone replacement in overall mortality, there does seem to - clonidine 0.1-0.2 mg bid 30-40% effective be a decrease in overall mortality. The benefit appears to decline with greater duration of use. But it appears that when women are on hormonal therapy for - avoid alcohol, caffeine, spicy foods more than 10 years they may experience increased breast cancer mortality and that is clearly an issue. The greatest benefit appears to accrue to those women who have coronary artery disease risk factors or established coronary artery Hormone Replacement Therapy and Prevention disease. HRT may have a role in prevention of: The benefits of estrogen in coronary heart disease are likely mediated through a variety of mechanisms. One very important mechanism is the beneficial effects on the lipid profile and other benefits. Overall mortality The cohort studies today, have consistently shown a substantial reduction in Osteoporosis relative risk of coronary heart disease. Some of the numbers from this body of evidence is there is about a 0.5 relative risk reduction. Longer therapy confers Coronary Heart Disease greater benefit. The addition of progesterone is not harmful with respect to the cardiac risk reduction. Stroke Coronary heart disease and HRT. Clearly, again we know that there is known protection from endogenous estrogens. The weight of evidence suggests that Cognitive function decline we reduce the risk of coronary heart disease in half. It is very clear that estrogen is of benefit in women who have established coronary heart disease. Colon cancer What is not so clear is how important it is to start estrogen therapy at the time of menopause and how long one needs to continue that benefit and whether Tooth loss benefit persists after discontinuing estrogen should one do so. Overall Mortality Osteoporosis is common in postmenopausal women. Other risk factors for osteoporosis include smoking and alcohol. They include low peak bone mass, low calcium intake, family history or osteoporosis and steroids and Users of HRT have a 0.63 relative risk of death hyperthyroidism. Sedentary life style is also on the list. So, those are things to consider in seeing an individual woman. Use of estrogen clearly decreases the Benefit decreases to 0.8 relative risk with more than 10 years of HRT due to risk of hip fracture. Remote use of estrogen does not confer the same benefit. If increased risk of breast cancer mortality. one looks at a woman who is on estrogen and examines her bone density 10 years after she stopped estrogen, she looks very much like a woman who never Greatest benefit accrues in those with risk factors for coronary artery disease. took estrogen at all. Coronary Heart Disease: Historically, it has been thought that it is best to start estrogen right at the time of menopause because the period of peak bone loss occurs in the perimenopausal and immediately postmenopausal period. There is some recent Known protective effect of endogenous estrogen evidence that suggests however that if you start estrogen in a woman 10 or 20 years out from menopause, she doesn't look all that different from a woman Observational cohort studies relative risk -0.5 who has been on it since the time that menopause started. The addition of progesterone does not appear to confer added benefit but also does not reduce Benefit as secondary prevention in women after CABG and angioplasty the benefit with respect to osteoporosis. It is thought that the minimum effective dose of Premarin or conjugated estrogen is 0.625 mg/day. There is Mechanism of benefit attributed to lipid effects, thrombotic mediators, vascular probably some benefit from lower doses, particularly if they are used in combination with other protective therapies like calcium and vitamin D. endothelium, platelets. Transdermal estrogen has similar efficacy with respect to osteoporosis Timing and duration of benefit not clear; there may be increasing benefit with protection, and that is in contrast to coronary artery disease where it is likely longer duration of use. (Helbert Arch Int Med 1997;157:1330). transdermal estrogen does not have the same beneficial impact as does oral estrogen. Other studies suggest that increased triglycerides attenuated with transdermal estrogen Osteoporosis: Stroke. Recent studies suggest that estrogen may decrease the risk of stroke. Epidemiology: vertebral fractures 25% women > age 60 hip fractures 25 % Similarly, a smaller number of studies done in Alzheimer's disease but with somewhat more impressive endpoints, particularly in recent studies. Hormone women > age 80 therapy tends to delay the onset of Alzheimer's disease and also improves function on complex neuropsychiatric testing and improves short-term Significant functional impact memory. A small number of studies suggest that one decreases the risk of colon cancer. Risk factors: lower peak bone mass, smoking, alcohol, lack of exercise, family history, low calcium intake, steroids, hyperthyroidism There are reports that estrogen increases the risk of breast cancer. It is clear that unopposed estrogen increases the risk of endometrial hyperplasia and HRT and osteoporosis: endometrial cancer with a 40% risk of endometrial hyperplasia after just two years of unopposed estrogen. The effect increases with increasing dose and increasing duration of estrogen therapy. The risk of death appears to be lower Observational cohort studies relative risk of hip fracture 0.6-1.0 ever use, 0.3-0.8 in women who develop endometrial cancer on estrogen than in women who current use develop it without estrogen. Estrogen actually increases bone density The PEPI studies again shed light on this and it has been the impression from observation studies for many years that the addition of progesterone essentially No demonstrated difference in adding progesterone 0.625 mg Premarin is eliminates this risk. With respect to the endometrial cancer, most physicians minimum dose required for benefit Transdermal estrogen has similar efficacy would not use unopposed estrogen any longer. If estrogen is used in combination with progesterone, the concerns about endometrial cancer are essentially nonexistent. Exercise, calcium and vitamin D should also be used Breast cancers are often estrogen sensitive and have estrogen receptors. Timing of use: Women with prolonged endogenous estrogen exposure are at increased risk of breast cancer. We worry about women with early menarche and nulliparous - greatest benefit from prolonged use women and animal models estrogen can induce tumors. - bone loss resumes at accelerated rate when estrogen stopped; risk of Looking at cohort studies, the suggestion has been that, in fact, estrogen does hip fracture near baseline > 6 years after stopping therapy increase the risk of breast cancer. The risk appears to be greater with longer duration of use. Stroke: relative risk in recent observational studies 0.7-0.85 though older study as Meta-analyses done of this question have suggested that the risks need not be high as 2.6 Alzheimer disease: relative risk may be as low as 0.4 as great as we were initially led to believe but certainly in women who are in Colon cancer: relative risk 0.5-0.9 particular risk groups - women with family history or women with benign breast disease - that there may some increased relative risk of breast cancer. Risks of HRT: A woman's risk of coronary heart disease is going to have an enormous impact Endometrial hyperplasia and cancer: on her risk of mortality. For the average woman with no special risk, one would anticipate that she Unopposed estrogen: would have extended life expectancy on hormones as opposed to not on hormones. Women with established coronary heart disease, women who are at relative risk endometrial cancer 2.3 risk for coronary heart disease, achieve a greater extension of life expectancy. A woman who has established coronary heart disease is more apt to benefit 40% incidence endometrial hyperplasia after 2 years of therapy than a woman who has risk factors but is not yet known to have coronary heart dose related disease. Women actually did live longer even if they are at some risk for breast cancer. Risk of death not equally increased; 90% 5 year survival vs 70% for cancers in non- Women who have a number of risk factors for breast cancer, one would project users they would have a decreased life expectancy but for all other women, one would project an improved life expectancy on hormone replacement therapy. Breast cancer: Women who had coronary heart disease risk factors or coronary heart disease and breast cancer risk factors still do better on HRT than not. That is I think the Physiologic evidence: best information available to help take this body of data and counsel a woman as to what she should do. estrogen sensitive breast cancers Estrogen contraindications. Women with undiagnosed vaginal bleeding should have that vaginal bleeding investigated before starting hormonal therapy and prolonged endogenous estrogen exposure increases risk specifically when it is to exclude endometrial hyperplasia and endometrial cancer as a source. Active thromboembolic disease. I would say that women correlated with higher bone density who have thromboembolic disease who are on anticoagulation can safely be treated with estrogen. Women with a history of DVT or pulmonary embolism Cohort studies relative risk 0.5-1.9 who are currently not anticoagulated, I would be concerned about starting that woman on estrogen. Meta-analyses relative risks: Active liver disease has been listed as a contraindication. I would view this as significant underlying liver disease with cirrhosis, minor LFT abnormalities are Ever use 1.0 not considered to be a contraindication. Breast cancer and endometrial cancer are contraindications. Family history 1.25-3.4 There is an increased risk of DVT and pulmonary embolism in women who are Benign breast disease 1.2-1.7 on these low doses of estrogen. Randomized control trials suggest that there may be a 2 to 4-fold increased risk of DVT and pulmonary embolus. This risk Nulliparity 1.5 disappears when estrogen is discontinued and it appears to be maximal during the first year of use. So, if you have been on hormones for a year and you haven't had a clot you are unlikely to develop one. Other adverse effects of HRT Relative contraindications. Family history of breast cancer, migraine increased incidence of cholelithiasis (oral estrogen only) nausea breast pain headaches. One should follow frequency of the migraines and just be aware headache mood swings bloating that migraines can become more frequent with hormonal replacement therapy. increased incidence of DVT/PE Hormones are not contraindicated in diabetics. In fact, diabetics should be - perhaps as much as 2-4 fold increased relative risk while on estrogen treated more aggressively with hormone replacement therapy because of their increased risk of coronary heart disease. Hypertension is not a contraindication. - maximal first year of use. Again, it is a risk factor for coronary heart disease. In the large populations, blood pressure does not appear to increase with low doses of estrogen used in HRT. Endometriosis and uterine fibroids are also not contraindications. Some Prescribing HRT would suggest that it is best to delay initiation of hormonal therapy in women with these conditions for a year or potentially more. Patients can develop Pharmacology: recurrent symptoms with estrogen but it is certainly not an absolute contraindication. Oral estrogens metabolized in liver (60-90% first pass) Adverse effects of HRT. Oral therapy will increase the risk of cholelithiasis. Transdermal estrogens have less effect on liver proteins Women may experience nausea, breast pain, headache, mood swings and bloating. Many women worry about weight gain. The PEPI trial suggested that women who are on hormonal therapy gain less weight than women who are Serum levels of estrogens lower in smokers than non-smokers menopausal and not on hormonal therapy. Contraindications: Practical aspects of prescribing. In a woman who has had a hysterectomy, current wisdom is that estrogen alone is all that one needs. Progesterone is undiagnosed vaginal bleeding really a part of regimens to protect against endometrial cancer. There is no body of evidence to date to say that progesterone adds benefit with respect to active thromboembolic disease coronary heart disease and bone density to a degree that it should be in these regimens. Women who have a greater risk must be on progesterone to prevent their risk of endometrial cancer. There are two general ways to do that. One is active liver disease cyclical therapy which is at the bottom of this slide and the other is continuous daily therapy with the same low dose of progesterone a day. breast cancer Premarin is used most commonly as the estrogen. Premarin is conjugated uterine cancer equine estrogen and is obtained from the urine of pregnant mares. In fact, that is the origin of the name Premarin - pregnant mare urine. The standard dose is Relative contraindications: 0.625 mg/day. The progesterone that is used is Provera or medroxyprogesterone acetate. There are a variety of ways that one can cycle women. The combination pill Premphase contains 0.625 mg/day and 5 mg of family history of breast cancer Provera for 14 days. If one is prescribing them separately, most folks would use 10 mg of Provera for 10 days. The combination tablet is actually less expensive migraine headaches than the two tablets purchased separately. Not contraindicated: The down side of cyclic therapy is that most women will continue to experience periods and will start to have periods if you initiate hormonal diabetes therapy many years after menopause. Vaginal bleeding is predictable, in contrast to what one experiences with continuous daily therapy. The bleeding tends to start between days 11 and 20. One should biopsy for unanticipated hypertension bleeding that falls outside that time frame. endometriosis The other option is continuous daily therapy. Prempro which is available as a single pill using a combination of these medications is Premarin 0.625 mg/day uterine fibroids and Provera 2.5 mg/day. The advantage of continuous daily therapy is that over the long haul most women will have amenorrhea. 70 to 80% have amenorrhea Post hysterectomy - estrogen only at the end of the first year. But still in the long term women are less likely to have withdrawal bleeding which would be true if they were on cyclic therapy. Forty to 60% will experience bleeding during the first six months of therapy. Combination therapy: That bleeding can be unpredictable and that is the downside of continuous therapy. cyclic therapy: Women should make their own decision on which regimen they prefer… daily conjugated equine estrogen (CEE, Premarin) 0.625 mg/d plus whether they are willing to put up with six months of erratic bleeding with the medroxyprogesterone acetate (MPA, Provera) 10 mg/day 1-12 hope that in the long term they won't experience any, or if they would rather Premphase has 5 mg medroxyprogesterone for 14 days (d 14-28) most experience have more predictable periods. They can switch from one regimen to the other withdrawal bleeding d 11-20; biopsy for unanticipated bleeding before day 6 certainly. In my experience and that of others, women who are put on this continuous daily regimen who are just recently through menopause tend to progestin have more bleeding than women who went through menopause earlier. A biopsy is necessary if a woman is still bleeding after six months of continuous continuous therapy: daily therapy. Premarin 0.625 mg/d plus Provera 2.5 - 5.0 mg/d The patch is not recommended because one will not achieve the same cardioprotective benefit with the patch. One of the major down-sides of the Prempro contains 0.625 mg CEE plus 2.5 mg Provera 40-60% breakthrough bleeding patch is that women who have not had a hysterectomy still need to be on in first 6 months progesterone so they still need to be on some hormonal therapy. 90% amenorrhea at 1 year For women who describe decreased libido, some have suggested that the biopsy for persistent bleeding at 6 months addition of testosterone may be of benefit. This has really not been studied intensively but there is a combination medication that is available. The dose of alternative estrogen: testosterone in this is quite low and likely it doesn't have significant side effects. ethinyl estradiol (Estrace) 1 mg equivalent to 0.625 mg Premarin Estratest HS (CEE 0.625 mg with methyltestosterone 1.25 mg) has been used to treat Indications of endometrial biopsy. A woman that is not having unexplained decreased libido vaginal bleeding does not need an endometrial biopsy prior to starting therapy. A woman who is on unopposed estrogen clearly does need annual endometrial biopsies. For women on combination therapy, women who are on cyclic alternative progesterone: therapy who have unanticipated bleeding or particularly heavy bleeding should have an endometrial biopsy. Women who have bleeding for more than six micronized progesterone - difficult to obtain - 100 mg bid or 200 mg qd day 1-12 months on low doses of Provera should also have an endometrial biopsy. norethindrone 0.35 mg X 28 days or 0.7 mg X 14 days Summary conclusions. Estrogen is very effective in treating the symptoms of Transdermal estrogen: menopause. For short term therapy in a woman who was not interested in the preventative benefits of estrogen therapy, roughly five years is reasonable, Must use progesterone in women with uterus avoids first pass effect no increase in followed by tapering of therapy. Abrupt discontinuation of estrogen may cause recurrent menopausal symptoms. Estrogen is of benefit in the vast majority of cholelithiasis attenuated rise in HDL levels no increase in triglycerides women because of the cardioprotective benefits and because of the decreased ?lower risk thromboembolic disease incidence of osteoporosis and fractures. Preparations: estradiol 0.05 mg qd If one looks at a woman who was remotely on estrogen and is no longer on Climara patches changed weekly estrogen, her body looks like that of one who was never on estrogen. Estraderm patches changed twice a week For a woman with risk factors for breast cancer and in whom one anticipates a Indications for endometrial biopsy: period of therapy for less than 10 years, it probably makes sense to delay initiation of therapy. If you are using this purely for preventive reasons you may wish to wait until she is 60 to initiate hormone replacement therapy. Baseline: No biopsy Cyclic HRT: Unanticipated bleeding before day 6 progestin and/or bleeding > 10 In the absence of major risk factors for breast cancer, it is useful to initiate a days Continuous daily therapy: very heavy bleeding or bleeding > 6 months discussion about the hormone replacement therapy and more likely not to start Unopposed estrogen: Annual biopsy it at the time of menopause. We may ultimately learn that it is best to wait awhile. With the women who opt not to start hormonal therapy at the time of Conclusions: menopause, it may ultimately be better to start a little more in their 60s and 70s. Estrogen is very effective in treating menopausal symptoms. Progestins protect against endometrial cancer. Most women would benefit from cardioprotective effects and reduced osteoporosis. minimum 5-10 years to prevent osteoporosis Short term use ( < 5 years) probably does not increase risk of breast cancer. Women at increased risk of breast cancer, may wish to limit use to <10 years. Delayed initiation of HRT (i.e. age 60) may prove to be a useful strategy. References Col NF et al. Patient -specific decisions about hormone replacement therapy in postmenopausal women. JAMA 1997;277:1140-47. Evans MP Fleming KC Evans JM. Hormone replacement therapy: management of common problems. Mayo Clin Proc 1995;70:800-805. Grady d et al. Hormone therapy to prevent disease and prolong life in postmenopausal women. Ann Int Med 1992; 117:1016-1037. Grodstein F et al. Postmenopansal hormone therapy and mortality. NEJM 1997;336:1769-75. Guidelines for counseling postmenopausal women about preventive hormone therapy. Ann Int Med 1992; 117:1038-1041. Coronary disease and HRT Grodstein F et al. Postmenopausal estrogen and progestin use and the risk of cardiovascular disease. NEJM 1996;335:453-61. Most recent f/u from the Nurses' Health Study. Manson JEet al. The primary prevention of myocardial infarction. NEJM 1992;326:14061416. The writing group for the PEPI trial. Effects of Estrogen or estrogen/progestin regimens on heart disease risk factors in postmenopausal women. JAMA 1995;273:199-208. Osteoporosis and HRT Felson DT et al. The effect of postmenopausal estrogen therapy on bone density in elderly women. NEJM 1993;329:1141-6.. Cauley JA et al. Estrogen replacement therapy and fractures in older women. Ann Int Med 1995;122:9. Tosteson AN et al. Cost effectiveness of screening perimenopausal white women for osteoporosis: bone densitometry and hormone replacement therapy. Ann Int Med 1990; 113:594-603. Endometrial cancer The writing group for the PEPI trial. Effects of hormone replacement therapy on endometrial histology in postmenopausal women. JAMA 1996;275:370-75. Breast cancer and HRT Steinberg et al. A meta-analysis of the effect of estrogen replacement therapy on the risk of breast cancer. JAMA 1991;265:1985. Venous Thromboembolism and HRT Vandenbroucke JP and Helmethorst FM. Risk of venous thrombosis with hormone- replacement therapy. Lancet 1996;348:972. See 3 accompanying articles same issue.