© may/june/july 1996

Menopausal Hormone Therapy

he term “hormone replacement therapy” is Tappropriate when used to describe the prescrip- tion of plus progestogens for a pre- menopausal woman who has had an oophorectomy. The use of these hormones after natural should be regarded as hormone therapy. After natural menopause it is essential that the specific goal of the hormone therapy is understood by both the patient and the physician and that the benefits outweigh the risks. • Definitions: Menopause (average age 51 years) is defined as • What are the indications for 1 year after a woman’s last menstrual period. hormone therapy? The 4-5 years before menopause when hormonal 1 Premature or surgical menopause concentrations are variable is called the peri- (before age 40) menopause. Vasomotor symptoms (hot flashes, etc.) These women have a clear hormone deficiency commonly begin during the perimenopause before state and need hormone replacement. Treatment menstruation ceases. should be continued to the average age of menopause (51 years) and then reassessed. • What are the initial goals of 2 Vasomotor and other menopausal care for the menopausal woman? symptoms. There are short-term randomized controlled trials • To educate and support women during the perimenopause to prepare them for this natural (RCTs) demonstrating that vasomotor symptoms, transition. respond to or progestin therapy. • To provide individualized advice regarding Patients with frequent and disturbing non-drug therapies which will maximize quality symptoms, particularly those that interrupt of life during the postmenopausal years. sleep, should be started on 0.3 mg of • To identify those patients who are most likely to daily and titrated to benefit from short or long-term hormone therapy. the lowest dose that controls the symptoms. When an effective treatment is found, choose • What are the important non-drug one of the appropriate convenient regimens below therapies? and continue it for a year; then try tapering and These therapies deserve more emphasis than drug stopping at least once a year. therapy (the estimated magnitude of the absolute 3 Urogenital atrophy. risk reduction from smoking cessation and regular Vaginal dryness, symptoms of urinary exercise is greater than that from hormone therapy). incontinence, frequency and urgency, and They should therefore be discussed and offered to frequent urinary tract infections can be all perimenopausal women. helped by local or systemic estrogen ther- • Education and support groups. apy.1 Initially try 0.5 cm (0.3 mg) of conjugated • Smoking cessation. estrogen applied to the introitus nightly for • Regular weight bearing exercise (walking 1 week and then once to twice weekly to maintain instead of driving, whenever possible). the effect. If the symptoms cannot be controlled by • Ensure daily calcium and vitamin D intake of low dose local therapy, it is better to use an oral ≥1.5 grams and 400 IU, respectively. regimen in the lowest effective dose.

The Therapeutics Initiative is at arms length from government and other vested interest groups. Our function is unbiased review and dissemination of therapeutic evidence. Assessments apply to most patients; exceptional patients require exceptional approaches. We are committed to evaluate the effectiveness of our educational activities using the Pharmacare database without identifying individual a physicians, pharmacies or patients. Please notify us if you do not wish to be part of this evaluation. 14 may/june/july 1996

• What are the side effects that limit • What are the most convenient oral the use of hormone therapy? regimens? Estrogens are contraindicated in patients with To maximize acceptability and compliance start with the a history of the following: cancer, lowest available dose and titrate up slowly to the final thrombophlebitis during pregnancy or with dose based on the patient’s symptoms and tolerability. oral contraceptives, severe migraine No : continuous or cyclic (calendar days 1-25) , active liver disease, or abnormal doses of estrogen only. menstrual bleeding. Adverse effects occur fre- With uterus: cyclic (calendar days 1-25) doses of quently with the onset of estrogen and/or progestin estrogen plus cyclic (days 15-25) doses of progestin. therapy. These include , breast swelling and In patients who prefer no menstrual flow, continuous tenderness, menstrual bleeding, headache, fluid daily low dose estrogen plus progestin (eg. 0.3-0.6 mg retention, and irritability. These effects often settle conjugated estrogens plus 2.5-5mg medroxyproges- with time or dosage reduction. terone acetate). In patients where estrogens are con- traindicated or not tolerated continuous daily prog- estin alone. (see Table 1).

Table 1: Drugs used in Hormone Therapy

Generic Name Trade Name Available Doses Daily Cost *

conjugated estrogens Premarin 0.3 mg $0.11 equine source 0.625 mg $0.17 0.9 mg $0.27 1.25 mg $0.28 conjugated estrogens CES 0.625 mg $0.13 tablet plant source 1.25 mg $0.20

Ogen 0.625mg $0.17 tablet 1.25mg $0.29

Estrace 1 mg $0.22 tablet 2 mg $0.38 ethinyl estradiol Estinyl 0.02 mg $0.09 tablet 0.05 mg $0.15

estradiol Estraderm patch 0.025 mg/day $0.67 patch 0.05 mg/day $0.72 0.1 mg/day $0.82

medroxyprogesterone Provera 2.5 mg $0.13 tablet 5 mg $0.26 10 mg $0.53 micronized progesterone Prometrium 100 mg $0.43˚ estradiol & norethindrone Estracomb patch 0.05 mg/day $0.74 ˚ patch 0.25 mg/day * Based on average cost to Pharmacare, 1995. ˚ Based on wholesale price. Non-Benefit at time of printing.

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• What is the evidence for benefits • What is the risk of endometrial and risks of long-term therapy? hyperplasia and cancer? There are no long term RCTs evaluating hor- The majority of 35 epidemiologic studies show mone therapy. Treatment decisions at present must be that the relative risk (RR) of is based on case control and cohort studies or short-term increased 2 to 8-fold with unopposed estrogen RCTs using surrogate endpoints such as bone mineral therapy. The predicted absolute risk of this effect is density or lipid measurements. Such studies are subject small as most endometrial cancers are curable to selection and other biases. Fortunately 3 RCTs are and the lifetime risk of dying of endometrial can- underway, so that better evidence should be available in cer is small (0.3%). Five studies have examined the the future2. effect of estrogen plus progestin and none have The best estimate of the benefits and risks of long-term shown a significantly increased risk compared to unopposed estrogen therapy can be obtained from the nonusers. Additional evidence is based on studies systematic review done by Grady et al.3 in 1992 (see demonstrating that progestins prevent the develop- Table 2). ment of endometrial hyperplasia in women taking estrogen.3,4 As a result of this evidence, in women with a uterus the addition of a progestin to estrogen therapy has become the standard therapy.

Table 2: Benefits and Risks of Long Term Unopposed Estrogen Therapy

Number needed Calculated Absolute Risk to treat for 10 years Conditions Relative Riska Change in 10 Years b to cause or prevent 1 event c

Coronary heart disease 0.65 - 0.8% 12 125 ∞ 0.96 0

9 fracture 0.75 - 0.4% 250

5 1.25 +0.6% 167

3,d d Endometrial cancer 8.2d +1.7% 59

a. Incidence of events in patients taking estrogen divided by incidence in patients never taking estrogen (from systematic review by Grady et al.3). b. The percentage risk in patients taking estrogen for 10 years minus the percentage risk in patients not taking estrogens and followed for 10 years (calculated from individual studies referenced). c. Reciprocal of absolute risk change. d. Risk is prevented by addition of a progestin.

• What is the risk of breast cancer? •Does hormone therapy prevent At least 45 studies have been done and the results are cardiovascular disease? inconsistent. Pooled estimates of use for <5 years do not Coronary heart disease and stroke are prevalent suggest any increased risk (RR 1.01). Pooled estimates of in postmenopausal women (lifetime probability use for 8 years or more reveal a relative risk of 1.25 46% and 20%, respectively) and are common (1.04-1.51).3 As a woman has a 10% lifetime causes of death (31% and 8%, at a median age of risk of developing and 3% risk of dying from 74 and 83, respectively). The data demonstrating breast cancer (median age, 69), this has sig- a benefit from unopposed estrogen in reducing the nificant consequences (see Table 2). The most risk of coronary heart disease gives a pooled rel- recent analysis of the Nurses Health Study5 showed a ative risk of 0.65 (0.59-0.71). Most of these stud- relative risk of breast cancer of 1.46 for women treated ies are done in women aged 45-60 years when for >5 years, and a similar risk for patients currently tak- the risk is low (small absolute risk reduction, see ing estrogen alone or estrogen plus progestin. This Table 2) and it is uncertain whether the benefit will study also showed an increasing relative risk with be maintained in older woman when the risk is increasing age. much higher. 14b may/june/july 1996

The Framingham Study showed an increased risk (median age, 79)3. A recent meta-analysis9 of the avail- with estrogen use which was predominantly seen in able literature on estrogen use gives pooled estimates of women over 60.6 Part of the beneficial effects the reduction in risk of hip fracture from case-control of oral conjugated estrogens is likely due studies, 0.57 (0.48-0.67), and cohort studies, 0.85 to positive effects on lipoprotein levels (LDL (0.68-1.07); The highest quality studies show the least and HDL); these are not seen with the protective effect of estrogen therapy. Even if the evi- estrogen patch.7 The addition of progestin dence is accepted and we pool all studies to get a RR of negates some of the beneficial increase in HDL:4 it 0.75, the absolute risk reduction is small. (table 2) is uncertain whether progestins will negate some of Estrogens also reduce the risk of vertebral and wrist frac- the benefit on coronary heart disease.The pooled tures3, which may cause significant morbidity.The ben- estimate for stroke does not show a benefit. efits probably outweigh the risks in patients with established (previous low • Does hormone therapy prevent trauma fracture) or patients with greater than fractures associate with osteoporosis? 5 risk factors for hip fracture10. Bone densitome- Menopause is associated with an accelerated try alone is not a useful screening test to identify patients decline in bone mass, which may lead to osteo- who would benefit from hormone therapy9,11. porosis and bone fractures in susceptible women. RCTs involving estrogens (equivalent to 0.625 mg • Conclusion conjugated estrogen) are uniformly positive in Education, support and non-drug therapies are essential attenuating the decline in estimated bone mass. A for all menopausal women. Short-term hormone therapy recent cohort study demonstrated that medrox- has a useful role in selected women with established yprogesterone plus estrogen therapy has a greater symptoms or disease. Until randomized trials are com- positive effect on bone mineral density thanestrogen pleted, long-term therapy decisions have to be made in alone.8.After cessation of estrogens the slope of the the face of uncertainty balancing the potential benefits decline in bone mass increases and bone mass and risks in individual patients.The final decision must reverts to its pre-treatment value. be guided by the individual woman’s choice. Only hip fracture has an effect on longevity; a The Ottawa Health Decision Centre has developed a deci- menopausal woman has a 15% lifetime chance of sion aid: ”Making Choices: Hormones after sustaining and 1.5% chance of dying of a hip fracture Menopause” which has been shown to improve a woman’s comprehension of the evidence and create realistic We would like to acknowledge the Obstetricians expectations. Practitioner and patient kits available. and Gynecologists, Endocrinologists and Family Tel: (613) 798-5555 ext.6183, Fax: (613) 761-5492 Practitioners whose thoughtful suggestions have E-mail: [email protected] Ottawa Health Decision Centre greatly assisted in the preparation of the final Loeb Medical Research Institute - Clinical Epidemiology Unit version of this Letter. Ottawa Civic HospitaL 1053 Carling Ave Ottawa ON K1Y 4E9 References: 1. Raz R, Stamm WE. A controlled trial of intravaginal in postmenopausal women with recurrent urinary tract infections. N Engl J Med. 1993;329:753-6. 2. Rosenberg L. Hormone replacement therapy: the need for reconsideration. Am J Public Health. 1993;83:1670-3. 3. Grady D, Rubin SM, Petitti DB, et al. Hormone therapy to prevent disease and prolong life in postmenopausal women. Ann Int Med. 1992;117:1016-1037. 4. Working Group for the PEPI trial. Effects of estrogen or estrogen/progestin regimens of heart disease risk factors in postmenopausal women. JAMA. 1995;273:199-208. 5. Colditz GA, Hankinson SE, Hunter DJ, et al. The use of estrogens and progestins and the risk of breast cancer in postmenopausal women. N Engl J Med. 1995;332:1589-93. 6. Stampfer MJ, Colditz GA. Estrogen replacement therapy and coronary heart disease: a qualitative assessment of the epidemiologic evidence. Preventive Medicine. 1991; 20:47-63. 7. Lufkin EG, Wahner HW, O’Fallon WM, et al.Treatment of postmenopausal osteoporosis with estrogen. Ann Int Med. 1992;117:1-9. 8. Grey A, Cundy T, Evans M, Reid I, Medroxyprogesterone acetate enhances the spinal bone mineral density response to oestrogen in late post-menopausal women. Clin. Endocrin. 1996; 44: 293-296. 9. University of Newcastle Osteoporosis Study Group. Final report: estrogen treatment - results of published trials and epidemiological studies, assessment of study quality and public health implications. July 1995. 10. Cummings SR, Nevitt MC, Browner WS, et al. Risk factors for hip fracture in white women. N Engl J Med. 1995;332:767-73. 11. Law MR, Wald NJ, Meade TW. Strategies for prevention of osteoporosis and hip fracture. BMJ. 1991;303:453-9. 12. Stampfer MJ, Colditz GA, Willett WC, et al. Postmenopausal estrogen therapy and cardiovascular disease. Ten year follow-up from the Nurses’ Health Study. N Engl J Med. 1991;325:756-62.

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