Clinical Review

From the Women’s Health Initiative to clinical practice: A 5-point plan

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A seasoned physician offers practical guidance on postmenopausal use of estrogen and progesterone.


 

References

KEY POINTS
  • Give estrogen and estrogen-progestin therapy only for the relief of significant vasomotor symptoms, and halt the therapy in all asymptomatic women.
  • Prescribe natural estrogens and progesterone whenever possible and measure serum levels to assess response and compliance.
  • Initiate therapy at a dose of 0.3 mg for conjugated equine estrogen, 0.5 mg for oral estradiol, and 0.035 mg for transdermal estradiol and progressively increase, if necessary, to no more than twice these amounts.
  • Give progesterone cyclically rather than continuously to reduce risk of cardiovascular disease, breast cancer, other adverse events.
  • Reassess regimens annually in each patient.
After our usual Saturday morning match, my tennis partner asked if I still prescribed estrogen and progestin therapy (EPT) for menopausal women. He had, of course, seen recent reports of the Women’s Health Initiative (WHI) findings (TABLES 1 and 2).1

I replied that most of my symptomatic postmenopausal patients continued taking estrogen therapy (ET) or EPT. Still, I understood the concern that prompted the question.

After the WHI findings became widely publicized, many women discontinued EPT—only to resume therapy 8 to 10 weeks later because of persistent vasomotor symptoms. A number of other postmenopausal women, however, were able to cope with the transient recurrence of menopausal symptoms. I was happy to encourage them to permanently discontinue ET/EPT, since the primary reason for starting the therapy (vasomotor symptoms) was no longer an issue and the secondary reason (long-term benefits originally attributed to therapy with estrogen and progestin) had been seriously challenged.

This article discusses the American College of Obstetricians and Gynecologists guidelines on ET/EPT,2 and includes 5 specific pointers on managing menopausal women at risk for osteoporosis, breast cancer, and cardiovascular disease.

The bottom line: The WHI has significantly affected clinical practice, but hormone use is not precluded in symptomatic post-menopausal women, whose distressing symptoms and quality of life are improved by EPT.

TABLE 1

Relative risk of selected adverse events in women taking estrogen-progestin therapy1

EVENTRELATIVE RISKCONFIDENCE INTERVALSTATISTICAL SIGNIFICANCE
Coronary heart disease1.291.02–1.63Yes
Stroke1.411.07–1.85Yes
Breast cancer1.261.00–1.59Yes
Pulmonary embolism2.131.39–3.25Yes
Endometrial cancer0.830.47–1.47No
Hip fracture0.660.45–0.98Yes
Colorectal cancer0.630.43–0.92Yes
Deep venous thrombosis2.071.49–2.87Yes
Vertebral fractures0.660.44–0.98Yes
Other osteoporotic fractures0.770.69–0.86Yes
Global index1.151.03–1.28Yes

TABLE 2

Number of selected adverse events per 10,000 woman-years1*

EVENTPLACEBO (N = 8,102)CEE/MPA (N=8,506)DELTA
Coronary heart disease30377
Stroke21299
Breast cancer30388
Pulmonary embolism8168
Endometrial cancer65-1
Hip fracture1510-5
Colorectal cancer1610-6
Deep venous thrombosis32616
Vertebral fractures159-6
Other osteoporotic fractures170131-49
Global index15117019
CEE = conjugated equine estrogen
MPA = medroxyprogesterone acetate
*Absolute risk
Not included in global index

1. Individualize treatment

In the realm of estrogen therapy, 1 size does not fit all. Women tolerate and respond differently to various preparations and doses. I tend to use estradiol and micronized progesterone as much as possible because I believe they may be safer. With natural hormones it also is easier to measure serum levels; this helps me assess a patient’s response to and compliance with therapy.

I prefer the transdermal preparation consisting of estradiol/norethindrone acetate (CombiPatch) because it is more physiologic and yields constant serum levels throughout the 24-hour day. In addition, it avoids the first pass through the liver, which is associated with nonphysiologic alteration of hepatic enzymes and proteins—especially binding globulins for steroids, thyroid and sex hormones, and coagulation factors.

2. Use the lowest effective dose to achieve benefits and avoid side effects

This is a critical recommendation. Although this rule should apply to all therapies, it is especially important for ET/EPT, which can be associated with life-threatening side effects.

In a prospective, observational study conducted in healthy postmenopausal women, Grodstein et al3 explored primary prevention of cardiovascular disease. They found that the relative risk of stroke rose with each incremental increase in the dose of unopposed conjugated equine estrogen (CEE). The relative risk of stroke with CEE at a daily dose of 0.3 mg, 0.625 mg, and 1.25 mg was 0.54 (95% confidence interval [CI], 0.28–1.06), 1.35 (95% CI, 1.08–1.68), and 1.63 (95% CI, 1.18–2.26), respectively. Thus, the lowest effective dose at initiation would be 0.3 mg for CEE. Comparable doses for oral estradiol and transdermal estradiol are 0.5 mg and 0.035 mg, respectively.

This dose may be progressively increased according to the patient’s response, but seldom should exceed double the starting dose. Similar guidelines should be followed for progestins.

3. Consider minimizing duration of progestin treatment

Prescribe ET for hysterectomized women and EPT for those with a uterus. This may seem like old advice, since all gynecologists know the importance of using EPT in women with a uterus. But the optimal formulation and administration of EPT remain elusive. It is now clear that not all progestins have the same physiologic effects—especially on cardiovascular health (see). For this reason, the type, sequence, dose, and duration of progestin administration should be carefully reevaluated.

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