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Menopause
Options for menopause...
SOME USEFUL FACTS AND RECOMENDATIONS ABOUT HORMONE REPLACEMENT THERAPY & SELECTIVE ESTROGEN RECEPTOR MEDULATORS (SERMS)
ALSO, please go to the link on the The Women's Health Initiative & Hormone Replacement Therapy FAQ for important information on long term use of hormone replacement therapy.
Breast Cancer and Hormones...
There appears to be a linear increase in the relative risk of breast cancer with increased duration of estrogen use (approximately 1-2% increase in relative risk per year of use). In women between the ages of 50 and 60 years, the absolute risk is approximately 6 excess cases of breast cancer per 1000 women over ten years. Again, there is concern that the progestin element of HRT may increase the risk of breast cancer when compared to women taking estrogen alone. Future studies will address this issue more fully. Of interest, so called '' designer '' estrogens receptor modifiers ( SERMS i.e. tamoxifen, raloxifene) that block estrogen receptors may decrease the risk of breast cancer and are used in prevention of recurrent breast cancer.
Venous Thrombotic (clotting) Events
The annual risk of deep vein thrombosis (DVT) in women over age 50 is approximately 1/1000. The risk increases to 3/1000 by the use of any estrogen-like drug,including all estrogens, tamoxifen and raloxifene. This risk although increased is very rare, but women with a history of clotting problems should not take hormone replacement therapy.
Endometrial Cancer (cancer of the uterine lining)
Unopposed systemic estrogen(without use of progesterone) in women with an intact uterus is not indicated as research has shown a 62% hyperplasia and other disturbed histology after 3 years. Hyperplasia may progress to atypical hyperplasia which is a precursor to cancer. Untreated women have a lifetime risk of endometrial cancer of 2-3%. Unopposed estrogen increases the relative risk of endometrial cancer by 5-10 fold. Adequate dose and duration of progestins reduces the risk to the level of women not taking estrogen and should be taken if estrogen is used.
Recurrent Myocardial Infarction (MI, heart attacks)
Extreme caution is advised in starting HRT in women with severe coronary heart disease (CHD) (e.g. post-Myocardial infarction (heart attack), severe stenosis by angiography, post-Coronary Artery Bypass Graft (CABG)). Internal Medicine and/or Cardiology should be consulted in the care of patients with these conditions before starting hormone replacement therapy. Patients with CHD currently receiving HRT do not need to discontinue HRT.
Hypertriglyceridemia (high blood lipids)
Oral estrogen in standard doses increases serum triglycerides approximately 20-25%. Progesterone tends to minimize this increase, but not completely. If baseline triglycerides are > 400-450, then transdermal (skin patches) estrogen may be indicated to avoid the possible increased risk of acute pancreatitis (inflammation of the pancreas). SERMS such as Raloxifene do not increase triglycerides and is an alternative for women at high risk for osteoporosis. It may increase vasomotor symptoms (hot flashes).
Gallstones/Liver Disease
The use of oral estrogen may carry a 1.5-2-fold increase in the risk of gall bladder disease. The risk of cholelithiasis (gall stones) increases with dose and duration of use. If a woman contemplating hormone replacement therapy and has mild liver disease, a transdermal estrogen preparation may be considered.
Contraindications of ERT/HRT
Absolute contraindications
- any recent cardiovascular event,
- known or suspected pregnancy,
- undiagnosed abnormal genital bleeding,
- active thrombophlebitis,
- severe liver disease,
- history of DVT or pulmonary emboli (PE) while on oral contraceptives.
Relative contraindications
- known or suspected breast cancer,
- endometrial cancer,
- gall bladder disease,
- history of DVT or PE unrelated to hormone use.
These contraindications are controversial and hormone replacement therapy may be appropriate in selected patients.
Special considerations when considering HRT for patients with cardiovascular disease...
Based on the Heart Estrogen Replacement Study (HERS) Study, in women with a mean age of 67 years with documented cardiovascular disease, initiating HRT may increase the risk of fatal and non-fatal myocardial infarctions within the first year of treatment. Although the HERS Study was designed to assess secondary prevention of cardiovascular events, it may have implications regarding recommendations for the use of HRT for primary prevention. This area is still very controversial and hormone replacement therapy may or may not prevent heart disease.
Observational studies of HRT show a reduction of 40-50% for primary prevention of cardiovascular disease. This has lead to prescribing recommendations for HRT. However, the cardioprotection reported in these observational studies may be the result of fundamental differences between women who take HRT and those who do not. They may have better metabolic risk factors before menopause, healthier lifestyles, be more educated and more likely to be compliant with medicationschedules.
Patients with a history of cardiovascular disease should be counseled about the available data and identifiable risk factors should be controlled before starting any therapy. Patients with a history of cardiovascular disease who are currently on HRT can generally be continued on their regimen.
OSTEOPOROSIS
The World Health Organization (WHO) defines osteoporosis: as a Bone Mineral Density (BMD) t-score < 2.5 standard deviations below peak bone density (t-score < -2.5 compared to an average 30 year old BMD).
osteopenia is a BMD t-score < -1.0 to -2.5.
Osteoporosis Assessment
Starting at age 45-55 all women should be counseled regarding osteoporosis. A formal risk assessment should be completed at approximately age 50, and re-evaluated at follow-up appointments.
Osteoporosis assessment is a review of risk factors, calcium intake and weight bearing exercise. Not every woman needs Bone Mineral Density (BMD) testing. The decision to test for BMD should be based on an individual's risk profile and testing is never indicated unless the results could influence a treatment decision.
Osteoporosis, a decrease in bone strength associated with decreased bone mineral density and microarchitectural deterioration of bone structure, is manifested by increased fracture risk. Over half of postmenopausal women will develop fractures. Fracture risk increases with age, doubling every 7-8 years.
Primary Risk Factors for Osteoporosis:
- Personal history of fracture as an adult (excluding finger, toes, head)
- History of osteoporosis or fracture (especially hip) in an adult first-degree relative
- Current cigarette smoking
- Low body weight (<127 lbs.)
Indications for Bone Mineral Density Testing:
Bone Mineral Density should be assessed at menopause in women with two or more of the primary risk factors for osteoporosis if they are not already on medications (HRT, SERM or bisphosphonate). In women without primary osteoporosis risk factors who are not on HRT or other osteoporosis therapy, it is cost-effective to consider BMD testing at age 60-65, not earlier. Again, testing is only indicated if it will affect decision making.
Women 70-79 years old who are not taking HRT or other osteoporosis therapy, but are willing to consider medication, may be screened with a single lateral spine film. This may reveal silent fractures in 20%-25% of these women and therapy may be initiated without further testing. Normal spine radiographs do not rule out osteoporosis in these patients. BMD testing may then be offered.
INDICATIONS FOR REPEAT BONE DENSITY TESTING:
Women with osteopenia or osteoporosis who are not on HRT or other osteoporosis therapy should have a repeat BMD no sooner than 2-3 years. Persons who start and continue any osteoporosis therapy do not require follow-up Bone Mineral Density. Patients on chronic corticoidsteroid treatment (>7.5 mg prednisone daily for > 3 months or equivalent) will require follow-up BMD tests. In patients with normal Bone Mineral Density, reassess in 6-12 months. Osteoporosis treatment should be initiated in these patients with a BMD t-score < -1, regardless of age.
TREATMENT OPTIONS
All perimenopausal and postmenopausal women should be advised to take at least 1000-1500 mg. of elemental Calcium from diet and supplements and 400-800 IU of Vitamin D (or ten minutes of skin exposure to sunlight) every day. Calcium and exercise are beneficial to bone strength, but are not equivalent to the benefits of estrogen. HRT is the first-line prescription for the prevention and treatment of menopausal osteoporosis. If there are no contraindications, HRT should be discussed with all post-menopausal women and the decision should be made in partnership between the woman and her provider. Women who cannot or choose not to take estrogen after counseling should be offered a Selective Estrogen Receptor Modulator (SERM) for a BMD t-score of < -2.5 or alendronate/etidronate for a BMD t-score < -3, even in the absence of other risk factors. In women 60 years of age or older with less severe bone loss, consider preventive treatment if multiple risk factors for osteoporosis are present, especially fracture. Women who are not candidates for estrogen or SERM therapy who have pre-existing esophagitis or gastroesophageal reflux disease (GERD) and therefore cannot take aldendronate, may best be treated with etidronate. Calcitonin generally should be reserved for patients who cannot tolerate first or second-line medications (HRT, SERMs, or bisphosphonates). In addition, patients with pain secondary to vertebral fracture may benefit also. Calcitonin offers no protection against hip fracture and has little long-term effect on bone. Referral to an expert is recommended where the use of 2 or more antiresorptive agents (HRT, SERM, bisphosphonates) is being considered. Prescription for prevention is only cost-effective in women ages 60 and older with BMD t-scores of -2.0 to -2.5 or less.
Raloxifene
Raloxifene 60 mg daily, is the first SERM to be released for prevention and treatment of osteoporosis and osteoporotic fractures in postmenopausal women. Itseffectiveness in reducing the risk of breast cancer has not yet been determined, although preliminary data are encouraging. Raloxifene lowers LDL to about the same degree as estrogen and raises HDL-2 (but not total HDL) about one half as much as estrogen. Neither a beneficial or adverse effect was seen on CHD after 3 years follow-up in about 7,700 osteoporotic women, compared to placebo. According to the recent MORE study, raloxifene decreases vertebral fractures by 40% in osteoporotic women. Its effects on non-spine fractures is small (9% risk reduction) versus alendronate or estrogen (20-25% risk reduction). It may increase hot flashes and other vasomotor symptoms.
Bisphosphonates: Alendronate & Etidronate
Alendronate is an option for women who cannot or will not take ERT/HRT). Alendronate has been shown to decrease hip, vertebral and wrist fractures by half in women with a prior vertebral fracture. In women with t-scores < -2.5 and no prior vertebral fracture, spine fractures were also reduced by 50%, but other fractures were only marginally reduced. For treatment of osteoporosis, the FDA approved dose is 10 mg po qd. Data suggests that 5 mg po qd* may also be effective for prevention and treatment of osteoporosis, and may cause fewer gastrointestinal side effects. The manufacturer states that there is a 20% incidence of GI side effects, primarily esophagitis.
A recent KPNC study found the incidence to be closer to 33%. Approximately 35% of patients may discontinue treatment due to these side effects. Advise the patient that 10 mg tablets should not be cut in half as cut tablets significantly increase esophageal irritation. Results from a recent study indicate that once weekly dosing of 70 mg is sufficient. This formulation is not currently available or FDA approved. Alendronate is contraindicated in patients with abnormalities of the esophagus, hypocalcemia, renal insufficiency (creatinine clearance < 35 cc/min), or the inability to stand or sit upright after dosing for at least 30 minutes. Etidronate is not FDA approved for the treatment of osteoporosis. However, it can be considered in patients who cannot take ERT/HRT or alendronate, when the BMD t-score is < -3. The dose is 400 mg qd for 14 days every 3 months and must be taken on an empty stomach.
Estrogen and the Brain
Estrogen deficiency may alter the threshold for clinical expression of various mood and cognitive symptoms. Patients may complain of fatigue, nervousness, headaches, insomnia and dysphoria. Several observational studies demonstrate that HRT reduces these symptoms in the perimenopausal period. The incidence of major depression does not increase with menopause. Several controlled trials demonstrate that hormone replacement therapy improved mood, cognitive function, and particularly verbal and short-term memory.
Alzheimer's Disease
Several recent epidemiological studies have suggested that estrogen deficiency may contribute to the development of Alzheimer's disease. These studies demonstrated a 40-60% reduction in the relative risk of Alzheimer's disease in patients taking estrogen replacement therapy.49,50,51 Although these studies suggest benefit and have been reported in the media, there is insufficient data at this time to make a statement about estrogen deficiency delaying the onset of Alzheimer's disease.
ESTROGEN DEFICIENCY & UROGENTIAL ISSUES
Lowered estrogen levels affect the female introitus, vagina and bladder with resultant thinning of the urogenital epithelium and reduction in vascular engorgement. This may affect sex and lead to urinary incontinence and relaxation of the pelvic floor.
Urinary complaints, including stress incontinence, urge incontinence and recurrent urinary tract infection are common among postmenopausal women, and occur as a result of both estrogen deprivation and tissue aging. The evidence of the beneficial effect of oral estrogen and/or topical estrogen on urinary incontinence is weak. However, there is subjective improvement in urogenital symptoms in many of these patients. Biofeedback-assisted and other behavioral training can be effective treatments for urge incontinence and may diminish symptoms of stress incontinence. Kegel's exercises in conjunction with local vaginal estrogen can be an effective treatment for urge and/or stress incontinence. At Kaiser Permanente South San Francisco we have a urogynecology clinic that may be helpful on a referral basis.
Estrogen Deficiency & Sexual Issues
Numerous lifestyle and non-hormonal factors may influence healthy sexual functioning. These include concerns about contraception, safer sex issues and coital urinary incontinence. Other confounding factors include relationship issues, body image, decreased libido, depression, stress and fatigue and lack of a functioning sexual partner. Various medications (including anti-depressants, anti-hypertensives) may have side effects that affect sexual functioning. Diabetes mellitus and peripheral vascular disease also need to be taken into consideration.
In most cases, systemic and/or vaginal hormone replacement therapy and the support of a concerned provider can deal with sexual concerns which develop in menopause. HRT increases blood flow to the genital area and relieves dyspareunia and vaginal dryness, as well as returning clitoral sensitivity to premenopausal levels. In addition, estrogen replacement may have an indirect effect on sexuality through its positive effects on mood and well-being.
Testosterone
Consider androgen (male hormone) therapy for women with decreased libido who do not respond to HRT or ERT alone. Unless there are extenuating circumstances, it should not be given without concomitant estrogen therapy. Evaluate for decreased libido and rule out other contributing factors such as depression, anxiety or marital problems. If a trial of testosterone is indicated, Testosterone 2% in velvacol applied to the peri-clitoral/labia minora q hs for 10 days and then 2-3 times/week thereafter or EstraTest(r)H.S. (Premarin(r) 0.625 mg and 1.25 mg of methyltestosterone) daily is suggested, along with behavior modification and a return to sexual activity. Allow 2 months for receptors to upregulate and behavior change to occur. If complaints persist, consider alternating Estratest(r) HS with Estratest(r) full strength, advancing to daily dosing as needed. If less estrogen is preferred, Halotestin 2 mg and estrogen (Premarin or Estrace) at the desired dose may be used. There is on-going research on the optimal preparation, dosage, length of treatment or long-term safety and delivery systems of testosterone replacement. Methyltestosterone is preferred over halotestin because of its ease in titrating dose and clearance.
Testosterone may lower HDL levels and may negatively affect the risk of cardiovascular disease. Baseline HDL/LDL and LFTs should be done and then repeated at 6 months. Symptoms of androgen excess such as hirsutism, skin and voice changes and clitoromegaly can occur, although the incidence is less than 5% with lowdoses.
Libido is complex. If HRT and testosterone therapy are not effective, further investigation into confounding issues may be necessary. It is important to determine the duration of a sexual problem, as long-term problems preceding perimenopause will likely require more intensive sexual counseling. Regular sexual activity when starting a testosterone regimine has the highest likelihood of success for the couple.
Other Prescription Medications to Control Hot Flashes
Clonidine inhibits the release of norepinephrine from the brain in a dose-dependent fashion and it can decrease hot flashes. The initial dose is 0.05 mg twice daily, but many women require at least 0.1 mg BID. Frequent side effects include dry mouth, palpitations, drowsiness, dizziness and hyptotension limit the usefulness of this medication. The clonidine patch (0.1mg/week)may be more acceptable.
Bellergal(r) (a combination of Phenobarbital, ergotamine and belladona) may be helpful for short-term relief of vasomotor symptom, but can cause sedation and the potential for habituation.4 Its use at bedtime can be helpful to improve sleep.
Synthetic Progestins may offer an effective alternative for relief of vasomotor symptoms in women in whom estrogen therapy is not appropriate or acceptable.
Options include:
- Medroxyprogesterone acetate (5 to 10 mg by mouth
- 150 mg IM of the depot form (depo-provera) every month, or
- Megestrol acetate (Megace) 20 to 40 mg QD
COMPLEMENTARY AND ALTERNATIVE THERAPIES FOR MENOPAUSE
Based on a review of the evidence, the strongest benefit exists for soy/phytoestrogens decreasing vasomotor symptoms, decreasing cholesterol and cardiovascular disease risk; ipriflavone slowing bone loss; calcium and vitamin D slowing bone loss and decreasing fracture rates in the elderly.
In the early years of menopause using soy proteins and plant-derived phytoestrogens (isoflavones), there is a modest decline in either the frequency or severity of vasomotor symptoms.59,60 20-25 grams of soy protein daily provides 60-75 mg of isoflavones and has been demonstrated to be better than placebo. This can be obtained by drinking 3 glasses of soy milk, eating a 1/2 cup of roasted soy beans a day or making a blender drink with 20-25 grams of soy protein powder. The FDA has recently approved labeling of soy protein products for decreasing cardiovascular disease risk and cholesterol levels There is insufficient evidence to determine whether soy proteins containing phytoestrogens improve or maintain BMD or decrease fracture rates.
Progesterone Cream
There is evidence that progesterone cream may decrease the frequency or severity of hot flashes, but does not preserve or improve bone density or lipid levels. Patients using over the counter progesterone/yam cream in conjunction with traditional estrogen replacement therapy should be counseled and treated as if they are on unopposed estrogen. It is important to counsel women about the use of so-called ''natural hormone'' preparations. Use of these creams may preempt the use of truly efficacious medications.
Natural Estrogens/Alternative Estrogens
Tri-est (80% estriol, 10% estrone and 10% estradiol) and Bi-est (80% estriol and 20% estradiol) are made by compounding pharmacies. There is no information regarding dosages and no FDA oversight regarding potency or quality control of these products. Much of their biologic activity may be derived from the more potent estrone and estradiol components. These preparations are expensive and they offer no advantage over standard HRT. Their use should be discouraged. Estriol is a very weak metabolite of estradiol. There is no data to support the notion that estriol provides protection from post-menopausal breast cancer, osteoporosis, cardiovascular disease or colon cancer.
Herbal Remedies
Many herbal remedies are classified as food or dietary supplements, not as drugs. Consumers often consider them to be inherently safe, even though they may have biologically active compounds. In addition, because they have not undergone thorough testing and quality is not regulated, doses can vary from batch to batch and contamination can occur.
Black Cohosh
There are no good randomized, controlled trials evaluating the effectiveness of this plant, which is found in a number of forms. Numerous open-label and/or non-randomized studies funded by the manufacturer of Remifemin (an alcohol extract of black cohosh root), found this specific product helpful in reducing the frequency of hot flashes and in alleviating mood disturbances in menopausal and perimenopausal women. No studies have been longer than 6 months. There were no significant side effects noted.
Dong Quai
One good quality clinical trial demonstrates no significant differences between dong quai and placebo for vasomotor symptoms, vaginal or endometrial effects. Side effects were limited to gastrointestinal gaseousness. There is pharmacological data that saffrol (contained in dong quai) is liver toxic. The significance of this is not known.
DHEA
There is inadequate evidence to make scientific conclusions about improvement in BMD, vaginal epithelial maturation, functional well-being or androgenic side effects in women. It is unclear whether DHEA adversely affects lipids, although 3 small studies have shown a significant decrease in HDL cholesterol.
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