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Menopause Matters

Progestins in Hormone Therapy: What Are the Options?

James H. Liu, MD

After the furor over postmenopausal hormone therapy that followed the Women’s Health Initiative (WHI), physicians are taking another look at estrogen/progestin combination approaches.

The findings of the WHI estrogen/progestin study in 20021 changed the clinical paradigm for menopausal hormone therapy (HT), leading to a reassessment of continuous daily estrogen/progestin therapy. This large, randomized trial demonstrated an association between estrogen/progestin use and an increase in coronary heart disease and breast cancer risks. In a subsequent WHI companion trial of hysterectomized women, estrogen-only use was associated with no increases in heart disease or breast cancer risks.2 Indeed, a stratified analysis of this trial indicated a reduced risk for coronary revascularization in women aged 50 to 59 years who received estrogen (hazard ratio [HR], 0.55; 95% CI, 0.35 to 0.86).3 Furthermore, calcified plaque in the coronary arteries was significantly reduced in this group.4

These latest findings support the hypothesis that initiation of estrogen therapy at the onset of menopause may play a protective role, whereas starting estrogen therapy in late menopause may enhance thrombotic risks. Taken together, these two trials also highlight the biologic impact(s) of the progestin component, which may play a major role in adverse clinical outcomes. For these reasons clinicians have a renewed interest in modifying the prescribing pattern for progestins in women who desire HT.

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PRINCIPLES

For women who have a uterus and desire HT, the clinician who prescribes progestin therapy should have the following objectives in mind:

• Preventing endometrial hyperplasia and endometrial cancer
• Improving compliance with HT by reducing the frequency of withdrawal bleeding and side effects associated with progestins
• Reducing overall progestin exposure that may have an adverse impact on target tissues such as the breasts and the cardiovascular system.

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ENDOMETRIAL HYPERPLASIA

Women using conjugated equine estrogens (CEE) alone, 0.625 mg, are more likely to develop simple cystic endometrial hyperplasia (27.7%), adenomatous hyperplasia (22.7%), or atypical adenomatous hyperplasia (11.8%) than those using placebo (less than 0.8%).5 By comparison, women who received lower doses of unopposed estradiol (1 mg/d) over 3 years had a 9.4% incidence of hyperplasia.6 In another study, women receiving CEE, 0.625 mg/d, alone experienced a hyperplasia rate of 8% per year, whereas the rate for a CEE dose of 0.45 mg/d alone was 3.23% per year. At the lowest CEE dose of 0.3 mg/d, the rate of hyperplasia was 0.37% per year.7 Collectively, these studies indicate a dose-response effect of unopposed estrogen on endometrial hyperplasia.

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PROGESTINS

Types

In general, progestins can be classified into two groups. Progestins derived from a 21-carbon skeleton are utilized primarily for HT and chemotherapy, whereas those derived from a 19-carbon skeleton (related to testosterone) are utilized in oral contraceptives (Table 1). The progestin drospirenone is an analog of spironolactone and has both progestin and anti-mineralcorticoid properties. This compound is available in a combination low-dose estrogen-progestin formulation. The route of progestin administration significantly influences its bioavailability. Oral formulations are not well absorbed and must be micronized to enhance bioavailability. The smaller particle size allows for more efficient absorption through the intestinal mucosa. Transdermal progesterone in cream preparations is not sufficiently absorbed to have clinical effects,8 whereas transvaginal preparations are well absorbed and preferentially transported to the uterus. Intrauterine delivery of levonorgestrel via an intrauterine device (IUD) is probably the most efficient option, and may induce regression of latent endometrial precancerous lesions.9

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TABLE 1. Classification of Progestins

The route of progestin administration significantly influences its bioavailability. Oral formulations are not well absorbed and must be micronized to enhance bioavailability. The smaller particle size allows for more efficient absorption through the intestinal mucosa. Transdermal progesterone in cream preparations is not sufficiently absorbed to have clinical effects,8 whereas transvaginal preparations are well absorbed and preferentially transported to the uterus. Intrauterine delivery of levonorgestrel via an intrauterine device (IUD) is probably the most efficient option, and may induce regression of latent endometrial precancerous lesions.9

Dose and Duration

In traditional cyclic HT progestins are prescribed for 12 to 14 days per month based on changes in biochemical endometrial markers and endometrial histology. Table 2 shows the therapeutic doses of commonly used progestins that will effectively induce secretory transformation of estrogen-primed endometrium when administered for 12 days.10,11

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TABLE 2. Progestin Potencies and Dosages Required to Induce Secretory Changes in Estrogen-Primed Endometrium

Prescribing Patterns

Current regimens for progestin administration are summarized in Table 3.

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TABLE 3. Prescribing Patterns for Estrogen-Progestin Hormone Therapy

Continuous Combined Estrogen-progestin Therapy—Continuous combined (CC) estrogen-progestin regimens have been the most studied in clinical trials. These regimens reduce the incidence of vaginal bleeding by inducing endometrial atrophy via daily progestin exposure. This approach results in a thin endometrium and a clinical amenorrhea rate of 85% to 94% after 1 year.12 However, this response is not uniform and some women experience unpredictable vaginal spotting. With CC regimens endometrial hyperplasia rates are similar to placebo.

As per FDA recommendations, patients who prefer a simple dosing regimen should be started on a low-dose CC regimen (Table 4). Although the progestin dose is lower than with cyclic regimens, the integrated monthly progestin exposure in CC preparations may be greater. No head-to-head comparative trials are yet available to determine whether there are any differences in outcome with low-dose CC formulations compared with standard CC regimens.

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TABLE 4. Continuous Combined Estrogen-Progestin Regimens

Cyclic Estrogen-progestin Therapy—In general, cyclic administration of progestins in sequential regimens is associated with monthly uterine withdrawal bleeding in a predicable pattern. The amount of bleeding may be less in women using low-dose estrogen. The cyclic regimen can be given in two ways (Table 3). Estrogen can be administered daily, adding a progestin on days 1 to 12 of every month. Bleeding usually occurs in the middle of the month. Alternatively, estrogen can be given from days 1 to 25 and progestin from days 14 to 25, with bleeding at the end of the month.

Long-cycle Estrogen-progestin Therapy—Long-cycle therapy was developed to improve adherence to HT and provide endometrial safety. These regimens consist of daily estrogen, with progestins administered at 2-, 3-, or 6-month intervals.13,14 Several studies have reported the feasibility of this approach (Table 5).14-17 In general, these protocols were tested in much smaller study groups than the CC estrogen-progestin regimens. Three of the studies demonstrate a fair degree of endometrial safety, provided the progestin is given for 14 days. Clinicians who utilize long-cycle therapy should:

• Consider using low-dose estrogens
• Carefully monitor the endometrium on a periodic basis (ie, at least yearly) with either ultrasonography or biopsy
• Counsel patients that long-term safety data are not yet definitive for long-cycle therapy.

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TABLE 5. Continuous Combined Estrogen-Progestin Regimens

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CONCLUSION

The WHI clinical trials demonstrate a potential benefit for early initiation of estrogen-only therapy at the onset of menopause. The use of CC estrogen-progestin therapy in the WHI was associated with increased risks of coronary heart disease and breast cancer, steering clinicians away from such regimens. This has led to a renewed interest in cyclic administration of progestins, either on a monthly basis or for longer intervals (eg, every 3 months). However, it must be remembered that clinical experience with long-cycle therapy is limited and additional trials are warranted.

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James H. Liu, MD, is Arthur H. Bill professor and chair, University Hospitals Case Medical Center, Departments of Obstetrics and Gynecology and Reproductive Biology, Case Western Reserve University, Cleveland, OH.

References

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