© U.S. Cancer Pain Relief Committee, 2002 0885-3924/02/$–see front matterPublished by Elsevier, New York, New York PII S0885-3924(02)00525-0

Vol. 24 No. 6 December 2002 Journal of Pain and Symptom Management 603

Clinical Note

Depomedroxyprogesterone Acetatefor Hot Flashes

Debra Barton, RN, PhD, AOCN, Charles Loprinzi, MD, Susan Quella, RN, BSN, OCN, Jeff Sloan, PhD, Sandya Pruthi, MD, and Paul Novotny, MS

Mayo Clinic, Rochester, Minnesota, USA

Abstract

To evaluate the efficacy of a long-acting preparation of medroxyprogesterone acetate for hot flash management, 3 men receiving androgen ablation therapy for prostate cancer and 15 women with a history of breast cancer were treated as part of clinical practice with three biweekly intramuscular injections of 500 mg depomedroxyprogesterone. A review of hot flash diaries and patient charts were completed to evaluate the effectiveness and tolerability of these injections for managing hot flashes. Treatment was associated with an approximate 90% decrease in hot flashes (95% CI 82–97%). Daily hot flash frequency decreased from a mean of 10.9 on the first day of treatment (95% CI 8.0–13.8 hot flashes per day) to a mean of 1.1 hot flashes 6 weeks later (95% CI 0.5–1.8 hot flashes) and to a mean of 0.7 hot flashes 12 weeks following therapy initiation (95% CI 0.1–1.2). Improvement in the hot flashes remained for months after discontinuing the injections in many patients. Reported side effects were minimal. This experience suggests that treatment with depomedroxyprogesterone may be an effective and well-tolerated option for the treatment of hot flashes.

J Pain Symptom Manage 2002;24:603–607

. © U.S. Cancer Pain Relief Committee, 2002.

Key Words

Hot flashes, depomedroxyprogesterone acetate, menopause, breast cancer survivors

Introduction

The decline of hormones in men and womendue to cancer treatment or as a result of naturalprocesses may cause a cascade of symptoms toerupt, with hot flashes representing one of themost prevalent symptoms. For women with a his-tory of breast cancer, the prevalence of hotflashes is reported to be over 50%.

1,2

For men un-dergoing androgen deprivation therapy for pros-tate cancer, the prevalence has been reported tobe between 35% and 75%.

3,4

The most commonly used treatment for hotflashes in women, estrogen replacement ther-apy, is not often employed in women with a his-tory of breast cancer. This is because of a fearthat estrogen might negatively affect breastcancer-related survival.

Megestrol acetate, a progestational agent, di-minishes hot flashes by approximately 80%.

5

This medication has been used successfully inboth men and women for 3 years and more incontrolling hot flashes.

6

However, the idea oftaking a hormonal agent for an extended pe-riod of time may not be an attractive option forsome. An alternative means used to provide aprogestational agent to relieve hot flashes wasdescribed in abstract form at the 1999 meetingof the American Society of Clinical Oncology.

7

Address reprint requests to:

Charles Loprinzi, MD, MayoClinic, 200 First Street SW, Rochester, MN 55905, USA.

Accepted for publication: January 19, 2002.

604 Barton et al. Vol. 24 No. 6 December 2002

In a randomized trial, three biweekly intramus-cular injections of depomedroxyprogesterone(DMPA) was compared to six weeks of oralmegestrol acetate (40 mg daily). There was atrend toward improved hot flash control withthe DMPA injections compared to megestrolacetate. Despite discontinuing the injectionsafter four weeks, hot flashes remained sup-pressed for months in some women.

Based on this information, as part of clinicalpractice, we began to use DMPA injections totreat men and women with hot flashes. This re-port describes our experience with 18 patientswho received DMPA injections for their hotflashes.

Methods

We reviewed the charts of 18 patients (15women with a history of breast cancer and 3men on androgen deprivation therapy forprostate cancer), for whom DMPA had beenprescribed for treatment of hot flashes. The 18patients included all of those who had beentreated with DMPA, completed daily diaries,and had given permission for their medicalrecords to be used for study. None of the pa-tients were concurrently receiving chemother-apy, androgens, estrogens, raloxifene, or otheragents for treating hot flashes. All of the menwere receiving leuprolide acetate therapy fortheir prostate cancer. Eight of the 15 womenwere receiving tamoxifen (all for at least onemonth prior to starting DMPA) during theirtreatment for hot flashes.

The patients treated with DMPA had all tried avariety of other agents for hot flash relief, includ-ing vitamin E, St. John’s Wort, soy supplements,venlafaxine, paroxetine, sertraline, megestrol ac-etate, estrogen, bupropion, clover extract, andBellaspas. Their hot flashes remained problem-atic despite these attempted antidotes.

Understanding that we were just beginningto utilize this therapy for hot flashes, and thatwe wanted to get a feel for how well it worked,these patients completed hot flash diary ques-tionnaires similar to those we have previouslyused in prospective clinical trials.

8,9

The diariesask for a daily total of mild, moderate, severe,and very severe hot flashes. Patients were con-tacted by phone at weekly intervals to ask aboutefficacy and toxicity. They were followed clini-cally for 12 weeks.

DMPA was prescribed at a dose of 500 mg in-tramuscularly every two weeks for a total ofthree doses. The patients started on this ther-apy between July 1999 and January 2000. Thisclinical case review was approved by the MayoFoundation Institutional Review Board.

Because this was not a randomized study, sta-tistical results are presented primarily as sum-mary measures with associated confidence in-tervals and graphical representations. Theprecision of efficacy estimates needs to be in-terpreted with caution due to the limitations ofthis clinical practice convenience sample.

Summary measures included the averagenumber of daily hot flashes and the mean dailyhot flash score. The hot flash score is a numberthat results from multiplying the number ofhot flashes in each severity category by a sever-ity rating of 1 for mild, 2 for moderate, 3 for se-vere, and 4 for very severe. These four num-bers are then summed. For example, if apatient had 4 mild hot flashes, 3 moderate, 1severe, and 1 very severe hot flash in a 24 hourperiod, their hot flash score would be 4

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17.Toxicity information was collected from clin-

ical charts and weekly phone calls. Addition-ally, a few patients wrote in some informationon their hot flash diaries.

Results

The 15 women ranged in age from 42–77years. The ages of men ranged from 68–78years. Seven women were younger than 50years old when their hot flashes began. Four ofthese 7 had received chemotherapy. None ofthe 15 women had evidence of active cancer.

Of the 18 patients, 1 woman did not get hersecond injection or complete her hot flash di-ary beyond week 4. Thus, 6 weeks of efficacydata was available on 17 patients, and 12 weeksof efficacy data were available on 15 patients.During the first 6 weeks, there were 18 dayswith missing values out of a possible 756, for a97.6% completion rate. During the entire 12weeks, there were 102 days with missing valuesout of a possible 1512 (93.3% completionrate). The missing values during the latter 6weeks were primarily due to three women, whostopped reporting after weeks 4, 8, and 10.One woman gave no reason for stopping herreporting, one said she stopped because she

Vol. 24 No. 6 December 2002 DMPA for Hot Flashes 605

had no hot flashes to report, and the other saidshe had infrequent mild hot flashes.

The efficacy of the DMPA therapy on hotflash frequency is illustrated in Figure 1, whichdemonstrates a dramatic reduction in hotflashes in the treated patients over the first fewweeks. The mean number of hot flashes for thefirst day was 10.9 flashes (95% CI 8.0–13.8 hotflashes) and the mean for day 42 (6 weekslater) was 1.1 hot flash (95% CI 0.5–1.8 hotflashes). The mean number of hot flashes onday 84 was 0.7 hot flash (95% CI 0.1–1.2 hotflashes).

The reduction in hot flash scores is remark-ably similar to the reductions seen in hot flashfrequencies (Figure 2), with virtually superim-posable curves. The mean hot flash score was18.7 on day 1 (95% CI 13.4–24.0), 1.8 on day42 (95% CI 0.7–2.8), and 1.3 on day 84 (95%

CI 0.2–2.3). Results for each individual patient(stream plots) for weekly hot flash scores are pro-vided in Figure 3. Thirty-three percent (6/18) ofthe patients reported no hot flashes at all byweek 6 and 67% (12/18) reported fewer thanone hot flash per day.

Hot flashes remained suppressed in many ofthe patients for months following completionof the three injections. The follow-up of the pa-tients ranged from 6 weeks to 8 months (me-dian 8 months). To date, 2 participants whoobtained hot flash relief with the initial injec-tions have had hot flashes recur and have re-quested additional DMPA injections 5 and 8months later.

Side effects primarily consisted of injectionsite reactions. Thirteen patients reported pain,swelling, and redness at the injection site,which dissipated over a few days. Isolated re-ports of other symptoms were also reported bypatients during the follow-up period. Cautionis urged with respect to labeling these as medi-cation-related, as this was not a placebo-con-trolled study nor was a standardized side-effectquestionnaire given to the patients. Nonethe-less, 2 patients stated they experienced weightgain, 2 reported muscular spasms, and therewas 1 reported instance of each of the follow-ing symptoms: vaginal spotting, weak finger-nails, depression, heart palpitations, food crav-ings, nightmares, headache, flu-like symptoms,insomnia, muscle spasms, increased bloodpressure, loose stools, and abdominal cramp-ing. Two patients also noted that they were eas-ily chilled. No thromboembolic events, edema,or episodes of hyperglycemia were reported.

Fig. 1. Mean daily frequency of hot flashes begin-ning with the day of the first injection through day85. Arrows indicate days of DMPA injections.

Fig. 2. Mean daily hot flash score beginning withthe day of the first injection through day 85. Arrowsindicate days of DMPA injections. Fig. 3. Weekly hot flash scores of individual patients.

606 Barton et al. Vol. 24 No. 6 December 2002

Discussion

The results of this clinical practice chart re-view support the findings of our Italian col-leagues,

7

strongly suggesting that medrox-yprogesterone acetate 500 mg intramuscularlyfor 3 biweekly injections is effective in reduc-ing hot flashes. The suppression of hot flashespersists for a considerable period of time afterthe injections are completed. The results forthis clinical experience are more profound thanthose seen in any of the hot flash studies wehave carried out to date.

5,6,8,9

Depomedroxyprogesterone acetate has beenpreviously studied for the relief of menopausalsymptoms in postmenopausal women. In onestudy, involving 48 women, 3 doses of DMPA(50, 100, and 150 mg) were compared to a pla-cebo.

10

Patients reported the greatest percenthot flash improvement, and were the most sat-isfied, with the 150 mg dose (reporting a 75–100% improvement in symptoms). Of the 12patients on the 150 mg dose, side effects weremild and generally occurred 1–2 weeks follow-ing the first monthly injection. Emotional labil-ity, weight gain, breast tenderness, and acnewere reported by 1–2 patients in this group.This was not significantly different from whatwas reported in the placebo group.

In another study, which compared 150 mg ofDMPA intramuscularly per month and salinein 57 patients, results were similar, with 89.5%of women receiving DMPA and 25% of thosereceiving placebo experiencing relief of symp-toms.

11

In this study, the main side effect wasabnormal vaginal bleeding (18/57 [32%] inthe DMPA group and 2/12 [17%] in the pla-cebo group). None of the reported side effectswere statistically significantly different betweengroups. Finally, in a study that compared de-pomedroxyprogesterone acetate 150 mg every25 days and conjugated estrogens 0.625 mg/day in 43 women, the DMPA-treated group re-ported an average 69% reduction in their hotflashes and the estrogen-treated group re-ported an average reduction of 61%.

12

Thirty-three percent of all women on DMPA reportedno vasomotor symptoms at 3 months, whereasonly 18% of the women on estrogen reportedno symptoms at three months.

12

An additional study, performed in 61 menreceiving androgen ablation therapy, used onedose of depomedroxyprogesterone acetate,

400 mg intramuscularly.

4

These men were fol-lowed for 6–36 months. Ninety-three percentexperienced a marked improvement in theirhot flashes and more than half only neededone injection. The efficacy of this responselasted from 4–12 months.

Some insight regarding the prolonged effec-tiveness of DMPA over several months is de-rived from the pharmacokinetic properties ofthis drug preparation. The drug, when deliv-ered intramuscularly, is present in plasma for 3weeks. With a half-life of about 50 days, thedrug is largely cleared over 120–200 days.

13

Itmight be that during this slow drop in serumMPA levels, the patient’s “temperature regula-tory setting” might gradually be reset, leadingto a hot flash-free state.

Is it safe to give progestational agents towomen with a history of breast cancer? Admit-tedly, a theoretical concern can be raised re-garding hormone therapy in breast cancer sur-vivors. However, no data currently exist todemonstrate that progesterones adversely af-fect breast cancer outcomes in breast cancersurvivors. In fact, doses similar to those we gavein this study have been utilized in the treat-ment of metastatic breast cancer.

14

Before concluding, we wish to again empha-size that the results of this report were derivedfrom a clinical experience situation, not a ran-domized clinical trial. As such, appropriate res-ervations need to be applied. The presentedinformation needs further study before beingcompletely endorsed.

In conclusion, DMPA appears to be a feasi-ble and reasonable treatment option to utilizein men and women suffering from hot flashes.These initial results are the most impressive wehave seen to date in testing ameliorative agentsfor reducing hot flash activity. The exact size ofthe effect needs further testing in a controlledsetting. In addition, the optimal dose andschedule of DMPA for controlling hot flashes isnot clear. Future studies are planned to at-tempt to better understand the efficacy andtoxicities of different doses and schedules ofDMPA for treating hot flashes.

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