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Therapeutics Letter, issue 14, May/June/July 1996

Menopausal Hormone Therapy


The term "hormone replacement therapy" is appropriate when used to describe the prescription of estrogens plus progestogens for a premenopausal woman who has had an oophorectomy. The use of these hormones after natural menopause 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 1 year after a woman's last menstrual period. The 4-5 year period before menopause, when hormonal concentrations are variable, is called the perimenopause. Vasomotor symptoms (hot flashes, etc.) commonly begin during the perimenopause before menstruation ceases.

What are the initial goals of care for the menopausal woman?

·         To educate and support women during the perimenopause to prepare them for this natural transition.

·         To provide individualized advice regarding non-drug therapies which will maximize quality of life during the postmenopausal years.

What are the important non-drug therapies?

These therapies deserve more emphasis than drug therapy (the estimated magnitude of the absolute risk reduction from smoking cessation and regular exercise is greater than that from hormone therapy). They should therefore be discussed and offered to all perimenopausal women.

·         Education and support groups.

·         Smoking cessation.

·         Regular weight bearing exercise (walking instead of driving, whenever possible).

What are the indications for hormone therapy?

1. Premature or surgical menopause (before age 40)

These women have a clear hormone deficiency state and need hormone replacement. Treatment should be continued to the average age of menopause (51 years) and then reassessed.

2. Vasomotor and other menopausal symptoms

There are short-term randomized controlled trials (RCTs) demonstrating that vasomotor symptoms respond to estrogen or progestin therapy. Patients with frequent and disturbing symptoms, particularly those that interrupt sleep, should be started on 0.3 mg of conjugated estrogens daily and titrated to the lowest dose that controls the symptoms. When an effective treatment is found, choose one of the appropriate convenient regimen below and continue it for a year; then try tapering and stopping at least once a year.

3. Urogenital atrophy

Vaginal dryness, symptoms of urinary incontinence, frequency and urgency, and frequent urinary tract infections can be helped by local or systemic estrogen therapy.(1) Initially try 0.5 cm (0.3 mg) of conjugated estrogen cream applied to the introitus nightly for 1 week and then once to twice weekly to maintain the effect. If the symptoms cannot be controlled by low dose local therapy, it is better to use an oral regimen in the lowest effective dose.

What are the side effects that limit the use of hormone therapy?

Estrogens are contraindicated in patients with a history of the following: breast cancer, thrombophlebitis during pregnancy or with oral contraceptives, severe migraine headache, active liver disease, or abnormal menstrual bleeding. Adverse effects occur frequently with the onset of estrogen and/or progestin therapy. These include nausea, breast swelling and tenderness, menstrual bleeding, headache, fluid retention, and irritability. These effects often settle with time or dosage reduction.

What are the most convenient oral regimens?

To maximize acceptability and compliance start with the lowest available dose and titrate up slowly to the final dose based on the patient's symptoms and tolerability.

No uterus: continuous or cyclic (calendar days 1-25) doses of estrogen only.

With uterus: cyclic (calendar days 1-25) doses of estrogen plus cyclic (days 15-25) doses of progestin. In patients who prefer no menstrual flow, continuous daily low dose estrogen plus progestin (eg. 0.3-0.6 mg conjugated estrogens plus 2.5-5mg medroxyprogesterone acetate). In patients where estrogens are contraindicated or not tolerated continuous daily progestin alone. (see Table 1).

Table 1: Drugs used in Hormone Therapy

Generic Name Trade Name Available Doses Daily Cost *
conjugated estrogens
tablet
All sources:

Premarin

CES
Congest

0.3 mg
0.625 mg
0.9 mg
1.25 mg
$0.11
$0.12
$0.27
$0.22
estradiol-17B (micronized)
tablet
Estrace 1 mg
2 mg
$0.22
$0.39
estropipate
tablet
Ogen 0.625 mg
1.5 mg
$0.18
$0.32
ethinyl estradiol
tablet
Estinyl 0.02 mg
0.05 mg
$0.10
$0.16
estradiol-17B
patch (3-day)
Estraderm patch 0.025 mg/day
0.05 mg/day
0.1 mg/day
$0.81
$0.87
$0.98
estradiol-17B
patch (3-day)
Vivelle patch 0.0375 mg/day

0.05 mg/day

0.075 mg/day

0.1 mg/day

$0.81

$0.92

$0.94

$1.04

estradiol-17B
transdermal film (7-day)
Climara 0.05 mg/day

0.1 mg/day

$0.79 !
estradiol-17B

vaginal drug reservoir (3-month)

Estring 0.0075 mg/day ??
estradiol-17B hemihydrate

vam-derived transdermal arm gel

Estrogel 1.5 mg ??
conjugated estrogen

vaginal cream

Premarin 0.625 mg $0.37
dienestrol

vaginal cream

Ortho Dienestrol
cream
0.1 mg/day $0.13
estrogen

esterified cream

?? 1 mg $0.38
Medroxyprogesterone acetate
tablet
Novo-Medrone 2.5 mg
5 mg
10 mg
$0.09
$0.19
$0.37
Medroxyprogesterone acetate
tablet
Provera 2.5 mg
5 mg
10 mg
$0.15
$0.29
$0.58
micronized progesterone
capsule
Prometrium 100 mg $0.47 !
estradiol & norethindrone
patch (3-day)
Estracomb patch 0.05 mg/day
0.25 mg/day
$0.92 !

* Based on average cost to Pharmacare, 1998.

! Based on wholesale price. Non-Benefit at time of printing.

What is the evidence for benefits and risks of long-term therapy?

There are no long term RCTs evaluating hormone therapy. Treatment decisions at present must be based on case control and cohort studies or short-term RCTs using surrogate endpoints such as bone mineral density or lipid measurements. Such studies are subject to selection and other biases. Fortunately 3 RCTs are underway, so that better evidence should be available in the future(2). Substantive data are only availablefor unopposed estrogen therapy; the best estimate of the benefits and risks of long-term unopposed estrogen therapyis presented in the systematic review done by Grady et al.(3) in 1992 (see Table 2).

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

Conditions

Relative Risk (a)

Calculated Absolute Risk
Change in 10 Years (b)

Number needed to treat for 10 years
to cause or prevent 1 event (c)

Coronary heart disease

0.65

-0.8% (12)

125

Stroke

0.96

0

---

Hip fracture

0.75

-0.4% (9)

250

Breast cancer

1.25

+0.6% (5)

167

Endometrial cancer

8.2 (d)

+1.7% (d) (3)

59 (d)

(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 endometrial hyperplasia and cancer?

The majority of 35 epidemiologic studies show that the relative risk (RR) of endometrial cancer is increased 2 to 8-fold with unopposed estrogen therapy. The predicted absolute risk of this effect is small as most endometrial cancers are curable and the lifetime risk of dying of endometrial cancer is small (0.3%). Five studies have examined the effect of estrogen plus progestin and none have shown a significantly increased risk compared to nonusers. Additional evidence is based on studies demonstrating that progestins prevent the development 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.

What is the risk of breast cancer?

At least 45 studies have been done and the results are inconsistent. Pooled estimates of use for <5 years do not suggest any increased risk (RR 1.01). Pooled estimates of use for 8 years or more reveal a relative risk of 1.25 (1.04-1.51).(3) As a woman has a 10% lifetime risk of developing and 3% risk of dying from breast cancer (median age, 69), this has significant consequences (see Table 2). The most recent analysis of the Nurses Health Study (5) showed a relative risk of breast cancer of 1.46 for women treated for >5 years, and a similar risk for patients currently taking estrogen alone or estrogen plus progestin. This study also showed an increasing relative risk with increasing age.

Does hormone therapy prevent cardiovascular disease?

Coronary heart disease and stroke are prevalent in postmenopausal women (lifetime probability 46% and 20%, respectively) and are common causes of death (31% and 8%, at a median age of 74 and 83, respectively). The data demonstrating a benefit from unopposed estrogen in reducing the risk of coronary heart disease gives a pooled relative risk of 0.65 (0.59-0.71). Most of these studies are done in women aged 45-60 years when the risk is low (small absolute risk reduction, see Table 2) and it is uncertain whether the benefit will be maintained in older woman when the risk is much higher.

The Framingham Study showed an increased risk with estrogen use which was predominantly seen in women over 60.(6) Part of the beneficial effects of oral conjugated estrogens is likely due to positive effects on lipoprotein levels (LDL and HDL); these are not seen with the estrogen patch.(7) The addition of progestin negates some of the beneficial increase in HDL(4): it is uncertain whether progestins will negate some of the benefit on coronary heart disease.The pooled estimate for stroke does not suggest any benefit.

Does hormone therapy prevent fractures associated with osteoporosis?

Menopause is associated with an accelerated decline in bone mass, which may lead to osteoporosis and bone fractures in susceptible women. RCTs involving estrogens (equivalent to 0.625 mg conjugated estrogen) are uniformly positive in attenuating the decline in estimated bone mass. A recent cohort study demonstrated that medroxyprogesterone plus estrogen therapy had a greater positive effect on bone mineral density than estrogen alone.(8) After cessation of estrogens the slope of the decline in bone mass increases and bone mass reverts to its pre-treatment value.

Only hip fracture has an effect on longevity; a menopausal woman has a 15% lifetime chance of sustaining and 1.5% chance of dying of a hip fracture (median age, 79) (3). A recent meta-analysis (9) of the available literature on estrogen use gives pooled estimates of the reduction in risk of hip fracture from case-control studies, 0.57 (0.48-0.67), and cohort studies, 0.85 (0.68-1.07); the highest quality studies showed the least protective effect of estrogen therapy. Even if the evidence is accepted and we pool all studies to get a RR of 0.75, the absolute risk reduction is small (see Table 2), estrogens also reduce the risk of vertebral and wrist fractures (3), which may cause significant morbidity. The benefits probably outweigh the risks in patients with established osteoporosis (previous low trauma fracture) or patients with greater than 5 risk factors for hip fracture(10). Bone densitometry alone is not a useful screening test to identify patients who would benefit from hormone therapy.(9),(11)

Conclusion

Education, support and non-drug therapies are essential for all menopausal women. Short-term hormone therapy has a useful role in selected women with established symptoms or disease. Until randomized trials are completed, long-term therapy decisions have to be made in the face of uncertainty balancing the potential benefits and risks in individual patients.The final decision must be guided by the individual woman's choice.


REFERENCES

  1. Raz R, Stamm WE. A controlled trial of intravaginal estriol 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 on 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, Whaner HW, O'Fallon WM, et al. Treatment of postmenopausal osteoporosis with transdermal estrogen. Ann Int Med. 1992;117:1-9.
  8. Grey A, Cundy T, Evanc 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.

We would like to acknowledge
the Obstetricians and Gynecologists, Endocrinologists and Family Practitioners whose thoughtful suggestions have greatly assisted in the preparation of the final version of this Letter.
The Ottawa Health Decision Centre has developed a decision aid: "Making Choices: Hormones after Menopause" which has been shown to improve a woman's comprehension of the evidence and create realistic expectations.
Practitioner and patient kit available.
Tel: (613) 798-5555 ext. 6183.
Fax: (613) 761-5492.
E-mail: ldrake@lri.ca
Ottawa Health Decision Centre
Loeb Health Research Institute
Ottawa Civic Hospital
1053 Carling Ave.
Ottawa, ON, K1Y 4E9

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