Treatment of Estrogen Deficiency Symptoms in Women Surviving Breast Cancer, Part 4

April 1, 1999

There are several million breast cancer survivors worldwide. In the United States, 180,000 women were diagnosed

There are several million breast cancer survivors worldwide. In the United States, 180,000 women were diagnosed with breast cancer in 1997, and approximately 97,000 of these women have an extremely low chance of suffering a recurrence of their cancer. With an average age at diagnosis of 60 years and a 25-year expected duration of survival, the current number of breast cancer survivors in the United States may approach 2.5 million women. Since breast cancer is now being detected at an earlier stage than previously and since adjuvant chemotherapy may cause ovarian failure, an increasing number of women are becoming postmenopausal at a younger age after breast cancer treatment. This conference was convened in September 1997 to consider how menopausal breast cancer survivors should be treated at the present time and what future studies are needed to develop improved therapeutic strategies. A total of 47 breast cancer experts and 13 patient advocates participated. The proceedings of the conference are being published in six installments in successive issues of oncology. This fourth part focuses on the treatment of urogenital atrophy, vasomotor instability, sleep disorders, and other related symptoms. [ONCOLOGY 13(4):551-575,1999]

Proceedings of a Conference, Held at the Boar's Head Inn, Charlottesville,Virginia, September 21-23, 1997

Frequency of Symptoms in Women With Breast Cancer

Patricia Ganz, MD: I will discuss two different studies focusing on the frequency of vasomotor symptoms and urogenital atrophy, respectively, in women surviving breast cancer. One study involved breast cancer patients recruited from the Los Angeles community and followed longitudinally during the first year after diagnosis.[1] The second study, conducted in Washington, DC, and Los Angeles, was a large, cross-sectional survey of breast cancer patients who were disease-free between 1 and 5 years after diagnosis.[2]

Symptom Profiles

In the first study, the average age of patients was 55 years; most had partners and were very well educated; and their ethnic distribution was representative of the breast cancer population in Los Angeles. Patients were interviewed at 1, 4, 7, and 13 months after diagnosis regarding their symptoms related to the climacteric.

For the purpose of this presentation, I have divided the sample into three age groups: women < 50 years; those 50 to 59 years old; and those ³ 60 years old. In women < 50 years of age, there was a relatively low rate of hot flashes at 1 month after diagnosis, with an increase to 45% at 7 months and a slight decline by 13 months. These findings likely represent the effect of chemotherapy in inducing premature menopause in these younger women.

The severity of hot flashes increased in women under age 50 as a function of time since surgery. For women over 50 years old, hot flash severity remained stable over the course of the 1 year of observation. These findings suggest that breast cancer treatment has an impact on ovarian function in younger women, but no hormonal changes probably occur in the older group.

It is likely that most women 50 to 59 years old had already entered menopause at the time of their breast cancer diagnosis. Many of these women could have been receiving hormone replacement therapy (HRT) at the time of diagnosis and stopped it thereafter. Some of these women (35%) were already experiencing vasomotor symptoms at 1 month after surgery; these symptoms increased in frequency at 7 months (60%) and persisted over the course of 1 year (55%).

Symptoms due to vaginal lubrication problems were available from sexually active women only. High rates of these problems were reported 1 month after surgery for all women independent of age (< 50 years old, 50%; 50 to 59 years old, 52%; ³ 60 years old, 57%), and these high rates persisted for up to 1 year. Since many of these women were postmenopausal at diagnosis, one cannot conclude that the therapy initiated for breast cancer treatment was causative. This finding led to more detailed studies focused on sexuality and intimacy in breast cancer survivors.[2] The older women stated that the severity of sexual problems was greatest early after diagnosis, with an improvement during the year of follow-up. Regardless of age, all women reported nearly the same severity of symptoms (hot flashes, lubrication problems) when evaluated at 1 year.

Sexual Functioning

In additional analyses of the same study sample,[1] we used the Cancer Rehabilitation Evaluation System (CARES) Sexual Functioning Scale (an 8-item measure) to assess sexual functioning. The youngest women reported the most disruption in sexual functioning initially after surgery; this improved somewhat over time but was still a persistent problem at 1 year. In the women 50 to 59 years old, sexual functioning scores at 1 month after surgery were intermediate between the youngest and oldest women, and their functioning did not change over time. In contrast, women over 60 years of age reported better sexual functioning initially (many were not sexually active with a partner), and this did not change over time.

These findings suggest that sexual functioning is disrupted to the greatest extent in the younger women, and that the reported dysfunction does not seem to recover after the breast cancer experience (ie, it does not improve with time since diagnosis).

Sexuality and Intimacy in Breast Cancer Survivors

In the second cross-sectional study,[2] our research group addressed the question of sexuality and intimacy in breast cancer survivors, with a special focus on whether sexual functioning would improve somewhat later after the breast cancer diagnosis. We reported on data from a large cross-section of disease-free patients living in Los Angeles and Washington, DC (N = 864).[2] On average, these women completed the survey 3 years after their breast cancer diagnosis. The women in this sample were similar medically and demographically to those in the first study.[1]

One issue that was addressed in this survey was the frequency of menstruation after breast cancer and the history of use of HRT. Only a small number of women continued to menstruate after their breast cancer diagnosis, and many (36%) had used HRT before being diagnosed. There was a divergence in HRT use between women living on the East and West coasts; a larger proportion of Los Angelean women reported a history of HRT use.

A symptom checklist was used to assess menopausal symptoms in this study sample. As shown in Figure 1, the prevalence and severity of hot flashes increased with age, and these symptoms were more frequent in the breast cancer survivors than in healthy volunteers participating in the National Surgical Adjuvant Breast and Bowel Project (NSABP) Breast Cancer Prevention Trial (baseline data obtained prior to randomization to tamoxifen [Nolvadex] or no tamoxifen).[3]

The breast cancer survivors who were < 60 years old appeared to show the greatest differences from the healthy comparison group. Hot flashes were less of a problem in women over 60 years old, but their severity was greater in the women with breast cancer than in controls. Although hot flashes were reported more frequently in breast cancer survivors, they were not extraordinarily severe.

With respect to urinary incontinence, the frequency of this complaint increased with increasing age (< 50 years old, 16%; 50 to 59 years old, 35%; ³ 60 years old, 40%). In both normal healthy women and those treated for breast cancer, these symptoms were not extremely severe.

When asked about vaginal dryness, only 20% of younger (35- to 49-year-old) healthy women reported this problem vs 45% of younger breast cancer survivors. The same trend was seen in older women, with breast cancer survivors reporting this problem more frequently.

Similar trends were noted with respect to pain during intercourse; younger healthy women reported less pain than did age-matched women surviving breast cancer. This symptom increased with age in both the healthy women and breast cancer survivors.

Sexual Functioning andQuality of Life

There is a similarity between our findings on sexual functioning in breast cancer survivors and data obtained from the Postmenopausal Estrogen/Progestin Intervention (PEPI) trial in healthy postmenopausal women.[4] When comparing our database with the PEPI data, age-matched scoring of sexual dysfunction scales did not differ between the two groups.[2] Both groups experienced a decline in sexual functioning with age.

Based on this finding, it is difficult to attribute most sexual dysfunction to therapy for breast cancer, as opposed to the normal effects of aging. This must be taken into account when conducting studies of sexual functioning in breast cancer survivors.

In addition, quality-of-life scores of breast cancer survivors on the Medical Outcomes Study, Short Form-36 (MOS SF-36) were equal to or better than scores of healthy, age-matched, control women.[2] These observations suggest that although breast cancer has an important effect on women’s lives, it does not translate into apparent decrements in their quality of life, as measured by standardized instruments.

Using data from this large cross-sectional sample, our group developed a model for examining sexual functioning that takes into account factors affecting women with breast cancer (eg, type of surgery, body image, chemotherapy, use of tamoxifen). In this multivariate model, the use of chemotherapy, discomfort with body image, and the presence of hot flashes predicted for poorer sexual functioning. Tamoxifen use was not associated with worse sexual functioning.

Characteristics of Women Taking HRT

Among 864 breast cancer survivors, only 44 (5%) were taking hormone therapy at the time of the survey. These women were somewhat older, largely white, more affluent, more frequently from Los Angeles, were experiencing more vaginal symptoms, and were more likely to have used estrogens previously. Use of tamoxifen and treatment with chemotherapy were not associated with current use of HRT.

Use of tamoxifen appeared to be associated with a favorable vaginal pH (ie, an estrogenic effect) and was not found to increase sexual dysfunction. Breast cancer survivors commonly reported use of herbs, soy, natural progesterone, and estriol for the treatment of various symptoms. They indicated a strong unwillingness to take HRT and said that they would only use hormonal therapy for relief of current symptoms, not for prevention of heart disease or osteoporosis. Most breast cancer survivors favored other alternatives, such as lifestyle changes, for the prevention of these medical conditions. One-quarter of breast cancer survivors stated that they would not take HRT under any circumstances.

Discussion

Elizabeth Barrett-Connor, MD, asked whether the women with milder symptoms were the same ones who said that they would never take HRT. Dr. Ganz replied that there was no relationship between symptom severity and willingness to take HRT. She also commented that women who had previously chosen to taken estrogens tended to be more likely to accept HRT use.

Bettye Green, RN, a patient advocate, expressed her belief that women do not take estrogens because of the great fear that they have of these hormones. According to Dr. Ganz, the fact that only 5% of the breast cancer survivors in her study actually took estrogens supports this point of view.

When asked whether exercise ameliorates menopausal symptoms, Dr. Ganz replied that no data are available regarding this point, but studies are warranted. A follow-up question addressed whether exercise appears to reduce the risk of primary breast cancer. Dr. Ganz noted that this seems to be true for menstruating women. Another participant hypothesized that regular exercise may reduce the level of circulating estrogen, but that this may not apply to postmenopausal women, unless exercise is associated with weight reduction and decreased aromatization of androgens to estrogens.

JoAnn Pinkerton, MD, commented that increases in symptoms of sexual dysfunction with increasing time after therapy may reflect the focus of the patient on survival initially and on quality of life later. Dr. Ganz responded that the appropriate way to assess this is to compare women who have survived breast cancer with healthy women to eliminate the confounding effect of aging.

Low-Dose Vaginal Estrogens for Urogenital Atrophy

Lisa Nachtigall, MD: Among 2,000 postmenopausal women in a given year, 20 will develop heart disease; 11, bone loss; 6, breast cancer; and 3, endometrial cancer, but nearly 100% will develop urogenital atrophy. Urogenital atrophy is not the first sign of menopause, but rather, occurs gradually after the onset of the climacteric. Although not life-threatening, vaginal atrophy, if left untreated, will persist and worsen as a woman ages.

Symptoms and Estrogen Therapy

Symptoms of urogenital atrophy include vaginal dryness, pruritus, dyspareunia, labial edema, dysuria, urinary urgency, pain, vaginal discharge, and urinary frequency and incontinence. Estrogen receptors are present in the vaginal epithelium, bladder, pubococcygeal muscles, urogenital ligaments, and pelvic floor muscles, explaining the diverse effects of estrogens on urogenital tissue. With estrogen therapy, there are changes in cytologic maturation, proliferation of vaginal and urethral epithelium, increased blood supply, decreased vaginal pH, relief of vaginal discomfort, improvement of urinary symptoms, and a decreased incidence of urinary tract infections. Estrogens restore the rugal folds of vaginal tissue and increase the number of superficial cells.

Estrogens can be given by multiple routes, all of which are effective. Consider the utility of estrogens given locally in the vagina and the possibility of local efficacy without systemic absorption of estrogen. Locally administered estrogen is effective at low dosage, avoids first-pass liver metabolism, and produces physiologic estradiol-estrone ratios. Vaginal estrogens, such as Premarin, Estrace, and Estring, offer an alternative for women who prefer nonoral therapy, or a possible option for breast cancer patients who have contraindications to systemic therapy. Vaginal creams produce serum estradiol levels that are one-quarter of levels produced by oral estrogen and yet are four times more potent than oral estrogens on the vagina.

A study by Mandel et al shows the gradual increment in vaginal maturation and increase in serum estradiol levels with topical conjugated estrogens (Figure 2 and Figure 3).[5] Increases in superficial cells and vaginal maturation index occur at levels of plasma estrogen that are barely above pretreatment levels.

A study by our group at St. Elizabeth’s Hospital examined vaginal pH at 1, 3, 6, 12, and 24 months after the initiation of vaginal estrogen therapy.[6] Within 1 month, pH normalized, and this effect persisted for 24 months.

Vaginal blood flow also increased continuously over the 2-year measurement period.

Plasma Estrogen LevelsWith Vaginal Estrogens

Data are scarce with respect to the safety of vaginal estrogens and the resulting plasma estrogen level. Mandel et al measured plasma estrone and estradiol levels in postmenopausal women receiving vaginal conjugated estrogens (Premarin; Figure 3).[5] Doses were gradually increased from 0.3 to 2.5 mg/d. Significant increases in systemic estradiol levels (from baseline) were detected. Yet, at the highest dose, estradiol levels were lower than those measured in premenopausal controls.

Similar results occurred with estrone, but the two lowest doses of conjugated estrogens did not cause a statistically significant increase in plasma levels, compared to baseline (pretreatment) levels. At the highest dose, estrone levels exceeded those measured in premenopausal women.

Oral vs Vaginal Estrogen

We compared the effects of oral estrogen with those of vaginal estrogen cream.[7] Plasma estradiol levels were markedly lower with the vaginal route. The disadvantages of vaginal methods include their irregular application intervals, bolus absorption (ie, short-interval, large-amount absorption in a noncornified vagina), and low absorption capacity of the fat-based vehicle, which necessitates the use of substantial amounts of emollient. This results in stickiness, messiness, and compliance problems.

To avoid these problems, the silastic vaginal ring (Estring) was engineered to deliver a small amount of estrogen vaginally. The first studies, conducted by our group[8] and by Bachmann,[9] compared a vaginal ring delivering 7.5 mg/d of estradiol with 1.25 mg of vaginal conjugated estrogens (Premarin) three times per week in 192 patients treated for 12 weeks.

The ring was equal to or better than vaginal conjugated estrogens with respect to such variables as vaginal secretions, vaginal color, vaginal tissue integrity, vaginal length, urethral meatus integrity, and patient acceptance. The vast majority (90%) of patients characterized the ring as extremely easy to use, while only 30% made the same comments about vaginal conjugated estrogens.

The study also addressed the issue of endometrial stimulation, using endometrial ultrasound and endometrial biopsy (for those with an endometrial lining > 5 mm), as well as progesterone challenge, as biological end points. Only 5% of women treated with the ring had endometrial thickness > 5 mm by ultrasound, as compared with 10% of those treated with the vaginal cream. Withdrawal bleeding after progesterone challenge occurred in 3% of patients who used the ring vs 21% of those who used the vaginal cream. Endometrial biopsy revealed stimulation in 5% of patients in the ring group and 10% in the vaginal estrogen group, but no patient in either group exhibited hyperplasia.

Several confirmatory studies in Europe demonstrated similar findings with respect to vaginal pH and vaginal maturation indices.[10] With respect to relief of symptoms, patients preferred the vaginal ring. Levels of estrone and estradiol increased initially when the vaginal mucosa was atrophic and allowed for better absorption. With maturation of the mucosa, absorption was markedly diminished, and levels of estrone and estradiol remained within the untreated postmenopausal range for up to 12 weeks of study (Figure 4).

Data on longer-term use will be forthcoming from our group in the near future.

Nonhormonal Therapy for Urogenital Atrophy

Nonhormonal therapy for urogenital atrophy consists of vaginal moisturizers and lubricants. The difference between the two is that a lubricant is used just prior to intercourse, whereas the moisturizer is used chronically as a means to improve symptoms. If used acutely, the moisturizer may be toxic to the partner or at least irritating if used just before intercourse.

A randomized, 12-week trial published by our group in 1994 compared the effects of a moisturizer, Replens, vs conjugated estrogen cream in 30 patients.[11] Replens was administered three times weekly with an applicator and conjugated estrogen cream was used at a dose of 1.25 mg/d.

By week 12, Replens reduced vaginal pH to 4.8, as compared with a pH of 4.4 with conjugated estrogen cream. The lower pH levels produced by estrogen probably are not clinically significant with respect to prevention of urinary tract infections, however.

With regard to vaginal elasticity, the estrogen produced statistically significantly greater effects at 4 weeks. Although Replens did increase vaginal elasticity over time, it took longer than estrogen to achieve this effect. Replens also reversed vaginal atrophy in 60% of patients, as compared with 100% receiving estrogen. Recornification occurred in all of the patients treated with estrogen but in none of the patients using Replens.

Discussion

Dr. Ganz commented that 60% of women over age 60 who were not taking estrogen did not complain of vaginal dryness. The important issue is the patient’s symptoms, not the objective evidence of atrophy; this issue is particularly important in breast cancer survivors. Women who are averse to risk want to control how much medication they take. This is possible with vaginal estrogen since they can use only the amount needed to relieve symptoms. They may initiate therapy by using the cream frequently but maintain the effects with less frequent dosage. With the vaginal ring, only one dose is used, and this may exceed what is necessary.

Dr. Nachtigall replied by indicating that the dose of estradiol delivered by the vaginal ring, 7.5 µg/d, is much lower than the lowest available dose of the vaginal estrogen creams (0.3 mg). Dr. Ganz pointed out that women may only use the cream once per week, and Dr. Nachtigall agreed that the cream does provide flexibility. However, she added that plasma estrogen levels are low in women using the vaginal ring, and acute absorption levels have not yet been studied in women applying the vaginal cream once per week.

Dr. Melody Cobleigh observed that another study using very low doses of vaginal estrogen demonstrated no increase in circulating plasma estrogens while demonstrating biological effects on the vagina and uterus. These findings indicate that very low amounts of estrogen are effective, and that the very high doses recommended in the Physicians Desk Reference, which tend to frighten breast cancer survivors, are not necessary.

Dr. Cobleigh also noted that the studies of the vaginal ring did not include quality-of-life measures and, of course, were unblinded. Dr. Nachtigall responded that these studies showed that patients found the ring easier to use and also preferred it to vaginal estrogen. In addition, when patients were asked to continue on the 2-year study, every patient agreed to stay on the ring, whereas a large dropout rate occurred among patients who were asked to continue using the vaginal estrogen cream.

Dr. Paul Goss asked whether the effects of the vaginal ring system were from systemic or local estrogen actions. Dr. Nachtigall responded that the effects are observed without any increase in systemic estrogen levels and, therefore, are likely to be purely local actions.

Dr. Pinkerton commented that her patients prefer the vaginal ring system over vaginal creams, but asked how one could prove the safety of the ring in women with breast cancer. Dr. Richard Santen noted that an ultrasensitive estradiol bioassay developed for research purposes[12] can measure estrogen levels as low as 0.02 pg/mL, as opposed to the 1- to 2-pg/mL levels detectable with very sensitive radioimmunoassays. It will be necessary to use this ultrasensitive assay to ensure that the vaginal ring does not deliver any estrogen systemically, he said.

Clarification was requested regarding estrogen absorption from an atrophic vs an estrogenized vaginal mucosa. Dr. Nachtigall confirmed that greater absorption occurs with atrophic mucosa, and, therefore, acute rises in estradiol can be seen upon initial exposure to estrogen. However, mature mucosa absorbs estrogen to a lesser extent. These phenomena explain the “burst” increase in plasma estradiol levels observed after insertion of the vaginal ring and the return to basal levels after 12 days.

When asked whether urinary incontinence and recurrent urinary infections respond to estrogens, Dr. Nachtigall replied “yes.” She also responded to a question regarding local estriol, indicating that this steroid is as effective as the vaginal ring when compared head-to-head. However, this product is not available in the United States.

Perspective of a Patient Advocate

Bettye Green, RN: The natural aging process results in symptoms, which need not be attributed to the treatment of breast cancer. In addition, many women surviving breast cancer will not take hormone replacement under any circumstances. These women must deal with the fact that they currently have breast cancer. They will not accept a hormone that may potentially prevent conditions that are not currently present but may (or may not) occur at a later time, namely, heart disease and osteoporosis. The prevention issue addresses a hypothetical problem, whereas the breast cancer is real.

Clinicians also need to keep in mind that only 15% to 25% of healthy women who do not have breast cancer choose to take hormones. Perhaps it is time to examine why this is the case.

Another issue is that a certain percentage of African-American women will never take hormone replacement. Many African-Americans view menopause as a normal passage of life, something to be expected, and therefore do not accept the need for treatment. Other issues include possible differences in estrogen receptor (ER) positivity between white and black populations, the development of breast cancer in African-American women at an early age, and the problems encountered when trying to enroll African-Americans in clinical trials

Also important are the difficulties in educating women (irrespective of ethnicity) effectively about the issues being discussed at this conference. The first step for clinicians is to understand which issues are important to patients and the second is to advise patients about those issues.

This raises the subject of communication. Women do listen to their physicians, but the ideal time to talk about symptoms of estrogen deficiency may not be during initial treatment, but rather, perhaps 6 to 12 months after the diagnosis, when the patient’s focus changes. Women do not like to be surprised by new symptoms and would like their physicians to inform them about possible side effects and later symptoms.

Perspective of Another Patient Advocate

Andrea Martin: Women encounter many sexual problems when they become menopausal, including loss of libido. None of the various options, ncluding Replens and testosterone, is completely effective in treating this problem. The helpfulness and cooperation of one’s partner are very important, as is acceptance of the problem.

Alternative approaches are available that are worth investigating. With the assault on the body that occurs with the diagnosis and treatment of breast cancer, the relaxation and vulnerability necessary for sexual relations can be very difficult to achieve. I personally found success with a very old Indian yoga practice called “tantra,” which involves commitment, communication, and consciousness. Eastern philosophies such as this are very similar to the methods used by sex therapists. A holistic approach can provide major benefits that hormonal or other medical and mechanical measures do not.

Discussion

Andrea Dunaif, MD, described studies conducted by her research team, which indicated that some women are more open than others about these issues and that there is a range of responses, from a willingness to forego sexual activity to a feeling that this aspect of one’s life is quite important. Measurement of testosterone levels in women with reduced libido can provide helpful information. When asked what level is considered normal, Dr. Dunaif replied that a level that is undetectable with standard assays would be considered meaningful, but a normal or elevated level would focus attention away from an endocrine problem.

Dr. Nachtigall mentioned a recent study demonstrating an improvement in libido with testosterone replacement but no change in sexual practice. This finding reinforces the concept of the behavioral and central nervous system (CNS) regulation of sexuality.

Dr. Barrett-Connor asked whether or not estrogens directly alter libido, as opposed to increasing libido by reducing discomfort secondary to urogenital atrophy. The consensus of the group was that there are no incontrovertible data to answer this question, and the data that are available are conflicting. Nelson Watts, md, noted that testosterone may not be completely safe because it can be aromatized to estrogen, which may be harmful in a patient with breast cancer. In response, it was pointed out that methyltestosterone and fluoxymesterone cannot be aromatized to estradiol, whereas other androgens, such as testosterone itself, do undergo aromatization.

Vasomoter Instability

Megestrol Acetate

Charles Loprinzi, MD: I will review data from the North Central Cancer Treatment Group (NCCTG), as well as from the Mayo Clinic, starting with a study published in The New England Journal of Medicine.[13] This double-blind, randomized, crossover trial compared megestrol acetate vs placebo in postmenopausal women and in men who had undergone a bilateral orchiectomy for prostate cancer. Hot flash scores and number of hot flashes were the major end points. Patients graded the severity of hot flashes as mild, moderate, severe, and very severe, and these were assigned a numerical value from 1 to 4 (with 1 denoting mild hot flashes and 4, very severe symptoms). The hot flash score represented the addition of the numerical value of all hot flashes for a 1-day period (Figure 5).

During the first 4 weeks of placebo treatment, the number and severity scores of hot flashes decreased in men by 20%. This represented the expected effect of placebo, which in multiple other studies produced a 20% to 25% reduction in hot flashes. With megestrol acetate, the reduction in end points in the men was 75% to 80%. It took 2 to 3 weeks to reach maximum benefit.

Stopping the megestrol acetate and crossing over to placebo resulted in a recurrence of hot flashes to approximately 50% of baseline levels after 4 weeks. Thus, initial control of hot flashes resulted in a later reduction that extended into the placebo crossover period. Men who were initially treated with placebo and then crossed over to megestrol acetate also experienced an 80% reduction in hot flashes following 4 weeks of treatment with the active drug.

The results in women were similar, with a 25% reduction in hot flashes with placebo and a 75% reduction with megestrol acetate. However, a short-term exacerbation of hot flashes was noted at the start of megestrol acetate, which persisted for a few days before a decline was observed. This occurred in the group initially receiving megestrol acetate, as well as in those who crossed over from placebo.

A separate analysis was done comparing the approximately 80 women who were receiving tamoxifen (Nolvadex) with the 20 who were not taking this hormone. Interestingly, only the women taking tamoxifen experienced the transient increase in hot flashes, but both groups had a reduction in symptoms when they used megestrol acetate for a longer period. The number of women who were not taking tamoxifen, however, was quite small.

This study showed that, over the short term, megestrol acetate controlled hot flashes to the same extent as achieved by estrogens in other studies. In a subset of 132 patients contacted after a 3-year period, 9% stopped megestrol acetate and did not experience a return of symptoms, and 45% were still continuing to take the drug. Of the latter group, about 20% of patients were still taking the 40-mg daily dose prescribed initially, whereas 75% were taking £ 20 mg/d. Some patients chose to take 20 mg every 2 to 3 days for hot flash control. Rarely were patients taking higher doses. Of the 59 patients receiving megestrol acetate, 41% continued to report hot flashes, but only 5% reported several per day.

These data suggest that long-term use of megestrol acetate controls hot flashes. I start therapy with 40 mg/d for 1 month and try to titrate dosage downward thereafter. No data are yet available to indicate whether this medication has adverse or protective effects on the risk of breast cancer recurrence or the development of new breast cancers.

Clonidine, Vitamin E,and Phytoestrogens

In a study conducted by our group at the Mayo Clinic, transdermal clonidine (Catapres-TTS-1), which releases 0.1 mg of clonidine/24 h, was administered to 116 women. The clonidine patch produced a 20% greater reduction in hot flash frequency than did placebo. Side effects included dry mouth, constipation, and drowsiness.[14]

Crossover data showed a 25% initial reduction in hot flash frequency with placebo and a further decline to 40% when patients were switched to clonidine. This represented a statistically significant reduction.

Another study compared vitamin E (800 IU/d) with placebo in 115 patients. Compared with placebo, vitamin E produced a statistically significant, but minor, change in hot flashes, equivalent to one hot flash reduction per person per day.[15]

Ongoing trials are examining the effects of phytoestrogens.

Veralipride

Veralipride, an agent used widely in Europe, is an antidopaminergic agent related to sulpiride and metoclopramide. Its hormonal effects include increases in prolactin, estradiol, and dehydroepiandrosterone (DHEA) sulfate; decreases in luteinizing hormone (LH) and follicle-stimulating hormone (FSH); and symptoms of galactorrhea and breast tenderness. Analyzing the data regarding hot flash reduction, I am convinced that the drug decreases hot flashes. Several trials support this contention.[16-19]

Serotonin Reuptake Inhibitors

The use of serotonin reuptake inhibitors is currently under study in several trials conducted by the NCCTG and at Georgetown and Bowman Gray/Wake Forest. In addition, our group at the Mayo Clinic is conducting a phase II trial of one such agent, venlafaxine. Data from a pilot study demonstrate approximately a 50% reduction in hot flashes with this drug.[20] These data are of interest and have led to a placebo-controlled clinical trial.

Summary

In summary, megestrol acetate is effective and probably safe for short-term use but has not been studied sufficiently with respect to risk of stimulation of occult breast cancer metastases. Clonidine is somewhat effective but has side effects, and vitamin E is only minimally effective but does give the 20% placebo benefit and perhaps a little more. Serotonin reuptake inhibitors look promising; the jury is still out regarding phytoestrogens.

Discussion

Jerilynn Prior, MD cautioned about the potential for side effects with the serotonin reuptake inhibitors, and Dr. Loprinzi concurred, emphasizing the need for careful studies. RenaVassilopoulou-Sellin, MD, asked about mood changes with megestrol acetate. Dr. Loprinzi commented on the increase in appetite and weight gain but had no data on sleep quality. He noted that his group occasionally increases megestrol dose to 80 mg/d but not to higher levels because of the effects on appetite and weight gain.

Use of Tamoxifen Plus Estrogen

Trevor Powles, MD, PhD: Data from the tamoxifen prevention trial can be used to evaluate the effect of giving estrogen to patients who are already receiving tamoxifen.[3a] Currently, 840 postmenopausal women have been enrolled in this trial, and are receiving 20 mg of tamoxifen per day or placebo. Hot flashes were noted by 21% of women receiving placebo and by 42% of those receiving tamoxifen. Because of this, the trial allowed women to receive both tamoxifen and an estrogen. This enabled an analysis of the effects of tamoxifen alone vs the tamoxifen plus estrogen.

In 153 women, tamoxifen caused a 13% reduction in total cholesterol, but the addition of estrogen caused no additional effect. Similar interactive effects were observed for antithrombin-3 and for fibrinogen. With respect to effects on bone mass, tamoxifen alone caused a 1% increase in spinal mass. Estrogen plus tamoxifen increased this by another 2%.

The investigators concluded that the addition of estrogen to tamoxifen had no detrimental effects on the parameters measured. On some end points, such as bone, beneficial interactions were observed. It appears that the addition of estrogen to tamoxifen does relieve symptoms of hot flashes. However, there are no data regarding the effects of adding estrogen on tumor incidence.

Discussion

Dr. Powles was asked how he treats premenopausal women with severe menopausal symptoms secondary to ovarian failure induced by chemotherapy. Dr. Powles stated his belief that approximately one-third of the effect of chemotherapy in this setting results from the chemical castration and lowering of estrogen levels and the remaining two-thirds from the direct effects of chemotherapy. Thus, the use of estrogen under these circumstances might be appropriate if the patient were also receiving tamoxifen. Adjuvant therapy or treatment of advanced disease with tamoxifen is effective in premenopausal women even though estradiol levels increase to 1,000 to 2,000 pmol/L.

Based on this line of reasoning, Dr. Powles speculated that treatment with estradiol in postmenopausal women should not abrogate the effect of tamoxifen if the levels of estrogen achieved were only in the 300-pmol/L range. He cautioned, however, that no studies are available to support this contention.

Marcia Moore, MD, asked about the potential increase in the risk of deep-venous thromboses in women with cancer receiving both tamoxifen and estrogen. Dr. Powles responded that no differences in incidence of this complication were observed between groups, but the numbers are rather small.[3a] He also indicated that his group had conducted comprehensive analyses on platelet function, proteins C and S, and other clotting factors and had found no differences between women receiving tamoxifen alone and those receiving tamoxifen plus estrogen.

Dr. Santen questioned the assumption that the competitive stoichiometry between tamoxifen and estrogen is the same in premenopausal and postmenopausal women. Perhaps it would take a higher number of tamoxifen molecules to block estrogen action in postmenopausal as opposed to premenopausal women. He further commented that tumor cells can adapt to tamoxifen by developing the ability to respond to this agent as an estrogen agonist. Cells in culture can enhance their sensitivity to estradiol under certain circumstances. Based on this reasoning, perhaps it is necessary to test the assumptions regarding tamoxifen/estradiol stoichiometry experimentally in premenopausal and postmenopausal women.

Dr. Powles commented that many of the results obtained in his studies were the opposite of those expected, and agreed that the note of caution offered by Dr. Santen was justified.

Dr. Vassilopoulou-Sellin asked about clinical data on the occurrence of new breast cancers in women receiving tamoxifen alone vs tamoxifen plus estrogen. Dr. Powles responded that only 60 tumors have been detected in the whole study since 1986, and that the numbers are not large enough to address that question.[3a]

Joseph Ragaz, MD, asked whether the lowering of cholesterol levels persisted for the entire period of 8 years, and Dr. Powles responded in the affirmative.

Perspective of a Patient Advocate

Jane Ford: My remarks will focus on three issues: education, alternative therapies, and cost. These issues should provide food for thought and discussion and should be part of any consensus arising out of this conference.

With regard to education, the problem is that time is valuable, and medical insurance does not adequately cover the costs of educational interactions between physicians and patients. Education is an empowering tool and requires that each woman’s unique situation be addressed so that she can decide whether hormonal therapy is right for her. What vehicles need to be developed to allow for full education? Should this be achieved through the World Wide Web, educational resource centers, providing patients with lists of available resources, or other methods?

With regard to alternative or complementary therapies, women are bypassing the clinical environment in their search for these therapies. Studies need to be performed to assess alternatives to hormones, such as vitamin E, primrose oil, and other substances. Studies on relaxation, diet, avoidance of triggering factors, and control of the external environment are also needed.

The third consideration, cost, is not discussed commonly. This is of particular importance for women who do not have comprehensive insurance. Does the issue of cost leave them without the option of considering a particular therapy? Tamoxifen costs $2.00 per day, or nearly $5,000 for a 6-year course.

Discussion

Dr. Santen was asked to comment on an animal model for hot flashes that may aid in developing new therapies for this problem. He noted that the pathophysiology of hot flashes is largely unknown-a fact that impedes the rational development of new therapies. A new model was recently presented[21] that appears to reflect postmenopausal physiology. In this model, acute temperature increments (hot flashes) could be prevented by estrogen, and both tamoxifen and raloxifene (Evista) antagonized this protective effect of estrogen. This model could provide a means of testing the serotonin reuptake inhibitors and veralipride, Dr. Santen commented.

Perspective of a Another Patient Advocate

Mary Sue Douglas, RN: As a patient advocate and 9-year breast cancer survivor, I have first hand knowledge about the initial feelings of fear, anger, and loss of control experienced by women who are diagnosed with breast cancer and about the need to develop effective lines of communication with one’s physician. A key issue is allowing the patient to be a partner in the decision-making process.

This conference has emphasized that divergent ideas and approaches exist, and that full discussion and education are necessary. Many women do not wish to take hormone replacement after being diagnosed with breast cancer, and alternative ways of managing the problems of estrogen deficiency are important for these women.

It is difficult for women to communicate about such issues as sexual dysfunction, and, therefore, physicians should try to develop better methods for eliciting this information and educating patients, and for communicating the various therapeutic possibilities. Patients want to be heard, be cared for, and be partners in the decision-making process.

Specialists tend to center their attention on specific issues. Surgeons tend to focus on the key issues related to initial treatment and do not usually address concerns about estrogen deficiency or issues of fear, anxiety, and uncertainty. The team of physicians who interact with patients, including surgeons, medical oncologists, and radiation therapists, should devise means to ensure that all of the patient’s concerns are addressed. The nurse practitioner has a definite role in this process.

Alternative Regimens for Control of Menopausal Symptoms

Herbal Remedies

JoAnn Pinkerton, MD: Many women use herbs without the knowledge of their physician. Since 1994, botanical products may be sold in the United States as herbs or dietary supplements, provided that no health claims are made and that the products have not been proven to be unsafe. Hyperbolic advertising and unsubstantiated claims about herbal products are common. Quality control of these products is problematic, and data on their safety, effectiveness, and toxicity are lacking. Review of the medical literature reveals reports of kidney and liver failure caused by certain products.

In general, herbs have mild medicinal activity and are not meant to be used alone in people with serious illnesses. Common menopausal remedies used by women include Dong Quai, Ginseng, Black Cohosh, Chasteberry, DHEA, Melatonin, and St. John’s Wort.

Only limited studies are available to assess the efficacy of herbal products. A randomized double-blind trial in postmenopausal women recently showed Dong Quai to be no more effective than placebo.[22] The National Institutes of Health (NIH) is funding a study to determine the efficacy and safety of St. John’s Wort for the treatment of mild depression.

Herbs with known harmful effects include those that contain carcinogenic pyrrolizidine [alkaloids (eg, borage, borage oils, coltsfoot, comfrey, and life root) or those with hepatotoxic effects (life root, germander, chaparral, and some Chinese medicine combinations).[23] Eighteen cases of chaparral hepatotoxicity were reported to the FDA between 1992 and 1994.[24] Four patients developed cirrhosis and two had fulminant liver failure requiring liver transplantation. Kidney failure and kidney transplantation have also been reported with other Chinese herbs.[23]

Licorice in high doses can cause pseudoaldosteronism. Other herbs reported to be harmful include penny-royal, pokeroot (which can be fatal in children), sassafras (which contains the carcinogen safrole), and calamus (which contains the carcinogen cisisoasarone).

Physicians should routinely inquire about the use of dietary supplements and other products and be alert to potential adverse effects with products, combinations of products, contaminants, or interactions with other drugs. Physicians should monitor patients who are taking supplements with serial blood counts, chemistries, and liver function tests and should report serious adverse events to Medwatch.

If women choose to use herbs, physicians should recommend that they use only products that detail all of their ingredients and contain standardized extracts. The limited amount of research on these products and the importance of not relying on package claims should be stressed.[25]

Herbs should not be used by women who are pregnant, nursing, or planning pregnancy and should not be given to infants or children under 2 years old (the liver is immature and cannot detoxify toxins). It is recommended that patients not take any herb every day, as their effects may be cumulative. Patients also should be advised not to take a large quantity of any one preparation because we do not know how much is toxic.[25]

There is no information regarding the effect of herbs on breast cancer risk.

Wild Yam and Natural Progesterone

The controversy remains about wild yam and natural progesterone. Wild yam is thought to be helpful because it contains Desigenin, the initial compound used in the synthesis of progesterone contained in oral contraceptives. Marketing claims aside, the human body lacks the necessary enzymes to produce progesterone from yams. This is possible only in the laboratory. Thus, wild yam creams without United States Pharmacopeia (USP) grade natural progesterone are felt to be nonhormonal. Wild yam creams are currently being tested for efficacy.

Phytoestrogens

Phytoestrogens are isoflavone compounds found in plants. These isoflavones bind to estrogen receptors and have both estrogen-agonist and -antagonist properties. Soybeans are a rich source of the phytoestrogens genistein, daidzein, and glytein. Populations with high levels of soy intake have lower rates of coronary heart disease, breast cancer, and osteoporosis. However, research on soy is in its infancy. Animal studies[26] and early human studies[27] suggest that soy/isoflavones inhibit bone resorption and/or stimulate bone formation. Male cynomolgus monkeys fed high-soy diets showed a marked reduction in coronary artery disease, with an estrogen-like effect on coronary artery reactivity.[28]

A recent meta-analysis by Anderson et al assessing the effect of soy on cholesterol in humans revealed that 47 g/d of soy was associated with a 12.9% decrease in low-density lipoprotein (LDL) cholesterol, a 9.3% decrease in total cholesterol, and no change in high-density lipoprotein (HDL) cholesterol.[29] Interestingly, the greatest effect was seen in individuals with the highest pretreatment cholesterol levels.

The relationship between soy intake and cancer risk is speculative. In animals, an inhibition of mammary and prostate cancer and tumor angiogenesis has been seen.

Two human studies presented at the second international symposium on soy[30,31] were unable to show a decrease in breast cancer risk with isoflavones. Petrakis et al[31] reported in- creased breast fluid (atypical cells) with soy, and Bundred et al[30] reported that breast biopsies showed increased breast cell DNA synthesis with soy.

The animal studies were more favorable. For example, rats exposed to genistein during early growth were less likely to develop mammary cancer,[32] and miso plus tamoxifen inhibited mammary cancer more than miso by itself.[33] High genistein intake was associated with fewer prostate tumors and less invasion. Korzenik et al[34] revealed that soy reduced bleeding in hereditary hemorrhagic telangiectasia, which suggests that soy may inhibit angiogenesis.

Regarding relief of menopausal symptoms, studies on the use of phytoestrogens show conflicting results, varying from little effect on hot flashes, to a significant reduction in hot flashes, to a reduction in the severity but not the frequency of flashes.[35,36] No definitive conclusions can be drawn.

Summary

Controlled clinical trials of alternative therapies have begun only recently. Herbal medicines may not be as safe as the public assumes. It is important to ask patients about their use of dietary supplements, herbs, and alternative approaches and to be alert to potential adverse effects or drug interactions. Phytoestrogens look promising, but the scientific information about their safety is lacking with respect to the risk of breast cancer.

Perspective of a Patient Advocate

Nina Rumen: I am a survivor of two breast cancers who has chosen to take estrogens to control symptoms of estrogen deficiency. Prior to being diagnosed with breast cancer at age 67, I had been taking Premarin for 14 years, and I stopped “cold turkey” at the time of diagnosis. I then received tamoxifen for 1½ years as part of a research study. I experienced severe menopausal symptoms, which I attributed to tamoxifen. These included hot flashes, bone disease (which required a hip replacement), symptoms of urogenital atrophy, and heart disease.

To manage these symptoms, I took clonidine, vitamin E, primrose oil, and Megace, all of which were either ineffective or produced side effects. Barrier cream and tricome cream did provide some relief of my genitourinary symptoms. However, after 2½ years of suffering with these problems, I decided to take Estraderm 50, which relieved all of my symptoms within 3 weeks and improved my outlook on life. Although I have only 40% to-50% of my usual energy due to my heart problem, I have great faith that pacemaker implantation and atrioventricular node ablation will improve my energy level. I plan to live until age 90. I am comfortable with the decision to take estrogens.

On the basis of my experience, I feel that there is a need for a team effort of physicians, nurse practitioners, and patients to educate breast cancer survivors about their options for relieving symptoms. If our country can afford to send astronauts up to the Mir space station, it certainly can afford a few educators.

Discussion

Jennifer Harvey, MD commented that the radiologist who performs core biopsies is often the one who initially tells patients about their diagnosis. She emphasized the necessity of training these specialists to handle this new role effectively. Dr. Harvey then raised the issue that hormone replacement causes increased breast density and alters the sensitivity and specificity of mammograms. This problem will need to be addressed in studies of HRT in women surviving breast cancer.

Michael Kleerekoper, MD, drew attention to the fact that many women view the estrogen-breast cancer decision as a yes-or-no proposition. They believe that if they take estrogen, they will develop breast cancer, and if they avoid using estrogen, they won’t develop this cancer. This misconception also requires education.

References:

1. Ganz PA, Schag CAC, Lee JJ, et al: Breast conservation versus mastectomy: Is there a difference in psychological adjustment or quality of life in the year after surgery? Cancer 69:1729-1738, 1992.

2. Ganz PA et al: Life after breast cancer: Understanding women’s health-related quality of life and sexual functioning. J Clin Oncol 16:501-514, 1998.

3. Ganz PA, Day R, Ware JE Jr, et al: Base-line quality-of-life assessment in the National Surgical Adjuvant Breast and Bowel Project Breast Cancer Prevention Trial. J Natl Cancer Inst 87:1372-1382, 1995.

3a. Powles T, Eeles R, Ashley S, et al: Interim analysis of the incidence of breast cancer in the Royal Marsden Hospital tamoxifen randomized chemoprevention trial. Lancet 352:98-101, 1998.

4. Greendale GA, Hogan P, Shumaker S, for the Postmenopausal Estrogen/Progestins Intervention trial (PEPI) investigators: Sexual functioning in postmenopausal women: The Postmenopausal Estrogen/Progestins Intervention (PEPI) trial. J Womens Health 5:445-458, 1996.

5. Mandel F, Geola F, Meldrum D, et al: Biological effects of various doses of vaginally administered conjugated equine estrogens in postmenopausal women. J Clin Endocrinol Metab 57:133, 1983.

6. Nachtigall LE, Nachtigall LB: The menopause, in Conn’s Current Therapy, p 1085. Philadelphia, WB Saunders, 1991.

7. Deutsch S. Ossowski R, Benjamin I: Comparison between degree of systemic absorption of vaginally and orally administered estrogens at different dose levels in postmenopausal women. Am J Obstet Gynecol 139:967-968, 1981.

8. Bachmann G, Notelovitz L, Birgerson L: A comparative study of low-dose estradiol vaginal ring and conjugated estrogen cream for postmenopausal urogenital atrophy. Prim Care Update Ob/Gyn 4:109-115, 1997.

9. Bachmann G: The clinical platform for the 17b-estradiol vaginal releasing ring. Am J Obstet Gynecol 178:5, 1998.

10. Holmgren PA, Lindskog M, von Schoultz B: Vaginal rings for continuous low-dose release of oestradiol in the treatment of urogenital atrophy. Maturitas 11:55-63, 1989.

11. Nachtigall LE: Comparative study: Replens versus local estrogen in menopausal women. Fertil Steril 61:178-180, 1994.

12. Klein KO, Demers LM, Santner SJ, et al: Use of ultrasensitive recombinant cell bioassay to measure estrogen levels in women with breast cancer receiving the aromatase inhibitor, letrozole. J Clin Endocrinol Metab 80:2658-2660, 1995.

13. Loprinzi CL, Michalak JC, Quella SK, et al: Megestrol acetate for the prevention of hot flashes. N Engl J Med 331:347-52, 1994.

14. Goldberg RM, Loprinzi CL, O’Fallon JR, et al: Transdermal clonidine for ameliorating tamoxifen-induced hot flashes. J Clin Oncol 12:155-158, 1994.

15. Barton DL, Loprinzi CL, Quella SK, et al: Prospective evaluation of vitamin E for hot flashes in breast cancer survivors. J Clin Oncol 16(2):495-500, 1998.

16. Fioretti P, Cagnacci A, Paoletti AM, et al: Effects of the antidopaminergic drug veralipride on LH and PRL secretion in postmenopausal women. J Endocrinol Invest 12(5):295-301, 1989.

17. Melis GB, Gambacciani M, Cagnacci A, et al: Effects of the dopamine antagonists veralipride on hot flushes and luteinizing hormone secretion in postmenopausal women. Obstet Gynecol 72(5):688-692, 1988.

18. Boulot P, Viala JL: A multicenter comparison of veralipride versus placebo in the vasomotor flushes of menopause: An evaluation of the prolonged effect. Rev Francaise de Gynecologie et d Obstetrique 83(12):823-827, 1988.

19. Verbeke K, Dhont M, Vandekerckhove D: Clinical and hormonal effects of long-term veralipride treatment in postmenopausal women. Maturitas 10(3):225-230, 1988.

20. Loprinzi CL, Pisansky TM, Fonseca R, et al: Pilot evaluation of venlafaxine hydrochloride for the therapy of hot flashes in cancer survivors. J Clin Oncol 16:2377-2381, 1998.

21. Merchenthaler I, Funkhouser JM, Carven JM, et al: The effect of estrogens and antiestrogens in a rat model for hot flush. Maturitas 30(3):307-316, 1998.

22. Hirata JD, Swiersz LM, Zell B, et al: Does Dong Quai have estrogenic effects in postmenopausal women? A double-blind, placebo-controlled trial. Fertil Steril 68(6):981-986, 1997.

23. Koff RS: Herbal hepatotoxicity: Revisiting a dangerous alternative. JAMA 73(6):502-503, 1995.

24. Sheikh NM, Philen RM, Love LA: Chaparral-associated hepatotoxicity. Arch Intern Med 157(8)913-919, 1997.

25. Tyler V: What pharmacists should know about herbal remedies. J Am Pharm Assoc NS36:29-37, 1996.

26. Arjmandi BH, Alekel L, Hollis BW, et al: Dietary soybean protein prevents bone loss in ovariectomized rat model of osteroporosis. J Nutr 126:161-167, 1996..

27. Lien LL, Lien EJ: Hormone therapy and phytoestrogens. J Clin Pharm Ther 21(2):101, 1996.

28. Anthony MS, Clarkson TB, Hughes CL, et al: Soybean isoflavones improve coronary heart disease risk factors without affecting the reproductive system of peripubertal rhesus monkeys. J Nutr 126:43-50, 1996.

29. Anderson J, Johnstone B, Cook-Newell M: Meta-analysis of the effects of soy protein intake on serum lipids. N Engl J Med 333:276-282, 1995.

30. Bundred NJ, Harding C, McMichael Phillips D, et al: Serum phytoestrogen concentrations in British women with breast cancer and controls. Am J Clin Nutr 68(6;suppl):1529S, 1998.

31. Petrakis NL, Barnes S: Stimulatory effects of soy protein isolates on breast fluid secretion (abstract). Am J Clin Nutr 68(6;suppl):1530S, 1998.

32. Peterson TG, Kim H, Barnes S: Genistein may inhibit the growth of human mammary epithelial (HLE) cells by augmenting transforming growth factor beta (TGFb) signaling (abstract). Am J Clin Nutr 68(6;suppl):1527S, 1998.

33. Ito A, Goto T, Yamanda K, et al: Primary prevention of cancers by miso, soybeans and biochanin A on rodent tumors (abstract). Am J Clin Nutr 68(6;suppl): 1525S, 1988.

34. Korzenik JR, Barnes S, Coward L, et al: Possible efficacy of isolated soy protein in treatment of hereditary hemorrhagic telangiectasia-associated epistaxis, gastrointestinal hemorrhage, and migraine: A pilot study (abstract). Am J Clin Nutr 68(6;suppl):1530, 1998.

35. Albertazzi P, Pansini F, Bonaccorsi G, et al: The effect of dietary soy supplementation on hot flushes. Obstet Gynecol 91(1):6-11, 1998.

36. Murkies AL, Wilcox G, Davis SR: Phytoestrogens. J Clin Endocrinol Metab 83:297-303, 1998.