Minimizing breakthrough bleeding

Schiff: We need more information about breast cancer and hormones, and we hope that future studies will provide that. But there is another potential risk of estrogen use that is better understood: the risk of endometrial cancer that comes with use of estrogen alone. With the publication of two important studies in December 1975, it became clear that giving estrogens to nonhysterectomized women had led to an increased incidence of endometrial cancer.^30,31 We then learned that adding a progestin to the regimen for 10 to 14 days per month would eliminate that increased risk. However, taking progestins in this way induced withdrawal bleeding in over 90% of nonhysterectomized women, and that has proved to be the second major reason for discontinuance.

Clearly, women do not want to continue bleeding after the menopause, particularly as they approach their 60s. To reduce or eliminate bleeding, it was suggested that estrogen and progestin both be given continuously throughout the month. Continuous dosage had been used with some success to treat endometriosis, and amenorrhea was noted in most cases. As a result, continuous combined regimens were introduced for hormone replacement and proved to be quite effective in reducing bleeding. Even with these regimens, however, spotting and breakthrough bleeding occurred, particularly during the first year.

Dr. Nachtigall, can you bring us up to date on how things stand now with continuous combined therapy and bleeding problems?

Nachtigall: In a sense, it’s really a matter of what the woman wants versus what the doctor wants. The doctor doesn’t want patients to get endometrial cancer, but the woman doesn’t want to bleed. That’s a problem for cyclic administration. The continuous combined regimen is a nice solution because it addresses both problems, but breakthrough bleeding can still occur. In fact, it can be more disturbing than the withdrawal bleeding of cyclic therapy because it’s unpredictable. So the goal is to use a formulation that is less likely to permit breakthrough bleeding.

Schiff: Have you found anything that works better?

Nachtigall: We’ve found that changing the progestin can make a significant difference. For example, combinations using NETA as the progestin component seem to induce less bleeding than the most common regimen using MPA. In fact, the combination of 0.5 mg of NETA plus 1 mg of estradiol has given us the best result for stopping hot flushes while at the same time minimizing bleeding [Figure 3]. As for keeping the doctor happy, endometrial biopsies showed that the women on this combination, even those who had breakthrough bleeding, stayed atrophic if they were atrophic before starting. There was no hyperplasia [Figure 4].

Schiff: Has this combination been compared directly with other combinations?

Nachtigall: Yes. In the Johnson study, 1 mg of estradiol plus 0.5 mg of NETA was compared head to head with the most commonly used continuous HRT combination, 0.625 mg of conjugated equine estrogens [CEE] plus 2.5 mg of MPA [Figure 1]. In the estradiol + NETA arm, 76.5% of the women were amenorrheic from the beginning, versus 68.3% of the women taking CEE + MPA. From cycles 4 to 6, the amenorrhea rates were 83.4% for estradiol + NETA and 78% for CEE + MPA. Endometrial protection was good for both combinations, at least for the short term.³²

Schiff: Some believe that patients on continuous combined therapy who have very irregular bleeding should have endometrial evaluation because of reports of endometrial cancer developing in such cases. What’s your experience with hyperplasia, Dr. Nachtigall? If you found no sign of hyperplasia with transvaginal ultrasound, would you still do a biopsy to evaluate the endometrium in a woman who had irregular bleeding 4 months after starting continuous combined therapy?

Nachtigall: If she’s on a continuous combined product of any kind, I usually can talk her through bleeding for the first 4 months. After that, bleeding is unacceptable because you’re not meeting your goal of amenorrhea. It’s also unacceptable because there are rare endometrial cancers that are genetically derived and aren’t prevented by progestin. If we ignore bleeding, we’re going to miss those. So I always investigate bleeding after the initial start, and I don’t allow it to continue after 4 months. I don’t expect women to be compliant when they bleed all the time. It’s asking too much.

Schiff: Dr. Berga, how do you handle breakthrough bleeding?

Berga: The American Cancer Society spent many years teaching the population at large that bleeding is a sign of cancer, so patients need to be reassured that they don’t have cancer. They become very nervous with just a few months of breakthrough bleeding, so you do have to evaluate it. Dr. Nachtigall is right about how long any woman will put up with bleeding. No matter how reassuring you are, you can’t talk women into wearing sanitary pads for the rest of their lives. Typically, that’s where most physicians run out of options, and that’s when patients discontinue therapy.

Schiff: How do you troubleshoot breakthrough bleeding?

Berga: There are a number of options. You can try a change in the estrogen or progestin, or both. You can also go back to a cyclic regimen, where the bleeding is at least predictable, or you can consider using a progestin-bearing IUD. Switching the route of administration is another possibility. Some people believe there’s less breakthrough bleeding with an oral regimen than with a transdermal product because of the hepatic effects of oral estrogen. I don’t know if that’s supported by data, but I will try an oral preparation at that point in a patient who has been on a transdermal regimen.

Schiff: Dr. Sarrel, is there anything you’d like to add about bleeding problems?

Sarrel: There are two points I’d like to make. The first is that, like Dr. Nachtigall, I’ve found that 1 mg of estradiol plus 0.5 mg of NETA is the most effective regimen for reducing bleeding. In all the studies, it’s the only combination that has achieved amenorrhea in 90% of women by the end of the first year of use. With 0.625 mg of CEE plus 2.5 mg of MPA, the percentage is about 68% at 1 year, and with 5 mg of ethinyl estradiol plus 1 mg of NETA, it approaches 80%.³³

The other point I want to address is the importance of taking pills as directed. In the WEST trial, we had the distinct advantage of using electronic monitoring to track adherence. Every time a woman opened the bottle to take her pill each day, that was electronically recorded.¹⁸In this study, we found that 80% of the irregular bleeding was due to noncompliance with directions; the women who had breakthrough bleeding were usually the ones who had not taken their pills for 3 or more days. Acute withdrawal of ovarian hormones leads to bleeding, whether it’s related to the menstrual cycle, or birth control pills, or HRT, so taking tablets as directed is crucial to avoid that sudden withdrawal.

Schiff: Considering the number of patients in your study who skipped pills and didn’t take them as suggested, it’s clearly important for us to emphasize adherence to directions from the start. Ideally, one wishes to minimize breakthrough bleeding when using a continuous combined regimen. Some agents have had better published results than others. It would be helpful at some point to have a randomized trial that compares the different agents head to head.