A randomized, placebo-controlled, double-blind study evaluating the efficacy of leuprolide acetate depot in the treatment of uterine leiomyomata*

FERTILITY AND STERILITY

Vol. 51, No.2, February 1989

Printed in U.S.A.

Copyright e 1989 The American Fertility Society

A randomized, placebo-controlled, double-blind study evaluating the efficacy of leuprolide acetate depot in the treatment of uterine leiomyomata* Andrew J. Friedman, M.D.t Debra Harrison-Atlas, C.N.M. Robert L. Barbieri, M.D.

Beryl Benacerraf, M.D.:j: Ray Gleason, Ph.D. Isaac Schiff, M.D.

Brigham and Women's Hospital, Harvard Medical School, and Diagnostic Ultrasound Associates, Boston, Massachusetts

Thirty-eight premenopausal women with uterine leiomyomata were enrolled in a randomized, double-blind, placebo-controlled study evaluating the efficacy of depot leuprolide acetate (LA), a gonadotropin-releasing hormone agonist, in decreasing uterine volume. Eighteen women received intramuscular (IM) depot LA 3. 75 mg every 4 weeks for 24 weeks (group A); 20 women received IM placebo with the same injection schedule (group B). Group A patients had a mean reduction in pretreatment uterine volume from 505 ± 93 cu em (mean ± standard error ofthe mean) to 305 ± 57 cu em after 12 weeks (P < 0.05 versus pretreatment) and 307 ±57 cu em after 24 weeks of therapy (P < 0.05 versus pretreatment). At 3 months after cessation of therapy, the mean uterine volume in group A had increased to 446 ± 92 cu em (P < 0.05 versus week 24). Group B patients had no significant change in uterine volume over the 24-week treatment period. These results suggest that depot LA therapy may significantly decrease uterine volume in patients with leiomyomata, but that regrowth of uterine size occurs shortly after cessation of therapy. Fertil Steril51:251, 1989

Uterine leiomyomata, commonly known as fibroids, are the most frequently occurring solid pelvic tumors in women. They occur in 20% to 25% of all women of reproductive age 1•2 and account for approximately 175,000 hysterectomies performed in the United States each year. 3 Leiomyomata are estrogen-sensitive, and high-estrogen states are associated with their growth. Many studies 4-8 have demonstrated that administration of gonadotropin-releasing hormone agonists (GnRHa) for 3 to 6 months induces a hypoestrogenic state, and causes reduction in uterine volume by 51% to 61%, on avReceived July 28, 1988; revised and accepted September 27, 1988. * Supported in part by a grant from Takeda-Abbott Research and Development, North Chicago, Illinois, and by grant 7-M01RR02635-01 from the General Clinical Research Center, Brigham and Women's Hospital. t Reprint requests: Andrew J. Friedman, M.D., Fertility, Endocrine and Menopause Unit, Brigham and Women's Hospital, 75 Francis Street, Boston, Massachusetts 02115. :j: Diagnostic Ultrasound Associates. Vol. 51, No.2, February 1989

erage. The cur.rent double-blind, placebo-controlled study evaluates the efficacy of a once monthly depot injection of the GnRHa, leuprolide acetate (LA), in decreasing uterine volume.

MATERIALS AND METHODS Patient Selection

Thirty-eight premenopausal women, 31 to 53 years of age, with leiomyomata uteri, voluntarily consented to participate in this study, which was approved by Brigham and Women's Hospital's Human Subjects Committee. Inclusion criteria were as follows: 1. Premenopausal with follicle-stimulating hormone (FSH) < 30 miU /ml; 2. Not pregnant or lactating; 3. Subject (or partner) had undergone prior surgical sterilization or agreed to use barrier contraception during the treatment period; Friedman et al.

Leuprolide depot therapy for fibroids

251

4. Presence of at least one fibroid measuring a minimum of 3 em in diameter, or uterus was at least twice normal volume with multiple fibroids on ultrasonic examination; 5. Uterus known to be increased in size for at least 6 months and did not grow more than 3 "gestational weeks" in size during the 6 months preceding entry into the study; and 6. No suspicion of ovarian, uterine, or cervical malignancy on physical or ultrasonic examination. Endometrial biopsy was performed on six women with a history of excessive bleeding, but none showed signs of neoplasia. In two women, biopsies revealed cystic and adenomatous hyperplasia, which reverted to normal on a second biopsy after treatment with medroxyprogesterone acetate 10 mg a day for 1 month. Protocol

Subjects were randomized to receive either LA depot 3.75 mg, (TAP Pharmaceuticals, North Chicago, IL; group A, n = 18) or placebo (group B, n = 20) intramuscularly (IM) every 4 weeks for 24 weeks. All patients and examiners were blinded with regard to treatment group throughout the study. Treatment was initiated during the first 3 days of the menstrual cycle. Patients were seen at 4-week intervals during the treatment period and at 3 months after cessation of therapy. During each visit, symptoms and menstrual histories were recorded. Blood samples were collected during the midluteal phase of the menstrual cycle before initiation of therapy, and at weeks 12 and 24, for determination of hematocrit, estradiol (E 2 ), progesterone (P), luteinizing hormone (LH), and FSH. Fourteen- to 16-hour fasting serum total cholesterol, high-density lipoprotein (HDL) cholesterol, and low-density lipoprotein (LDL) cholesterol concentrations, and routine serum chemistry tests were obtained at weeks 0 and 24. Steroid Hormone Radioimmunoassay (RIA)

All serum samples were stored at -2o•c until assayed by Endocrine Sciences Laboratory (Van Nuys, CA) for E 2 , P, LH, and FSH. Ultrasound

All patients had ultrasound performed within 1 month before initiation of therapy, after 12 and 24 weeks of therapy, and at 3 months after cessation 252

Friedman et al. Leuprolide depot therapy for fibroids

of therapy, by one radiologist (B.B.) using an Acuson 128 phased array variable focus system (Acuson, Inc., Mountview, CA) with a 3.5 MHz transducer. The uterus was measured in three dimensions: anteroposterior, width (across the widest part of the fundus) and length (from internal os to top of fundus). Calculation of Uterine Volume/ Statistical Analysis

Uterine volume was calculated as an ellipsoid by the formula (4/3) (1r) (R1 ) (R2 ) (R3 ), where R 1 , ~. and R 3 were the radii of each of the 3 uterine dimensions. The error associated with this calculation is greater in irregularly shaped uteri. Data were analyzed using one-way analysis of variance with comparisons of mean values between week 0 (pretreatment) and subsequent weeks tested for significance using Dunnett's t-test. Each treatment group was analyzed separately. Measure of dispersion is represented by the standard error of the mean. Reproducibility of bone densitometry measurements was determined using intraclass correlation, which represents the proportion of the variance of an observation due to subject-to-subject variability in error-free measurements. 9 Relation between change in uterine volume and other variables were tested for significance using standard Pearson product moment correlations. Bone Mineral i\,nalysis

Single photon densitometry was performed with a Norland Corporation Digital Bone Densitometer, Model #278A (Fort Atkinson, WI). Each patient had a triplicate measurement of the ultradistal radius within 1 month before initiation of therapy and after 24 weeks of therapy. This site contains approximately 25% cortical bone. The intraclass correlation for duplicate measurements performed on all patients was 0.859. RESULTS

Demographic data for both groups of patients are reported in Table 1. Randomization resulted in the groups being well matched for age, weight, Quetelet's index, and pretreatment uterine volume. In group A, all18 patients finished 12 weeks of leuprotide therapy, and 16 patients completed the 24week study. Two women discontinued therapy after 12 weeks because of severe hot flashes that began approximately 4 weeks after the first injection. Fertility and Sterility

Table 1

Table 2 Cholesterol Changes During Leuprolide and Placebo Treatment a

Demographic Data a Leuprolide (n = 18)

Age (years) Weight (kg) Quetelet's index (gm/sq em) Uterine volume (cu em)

41.4 ± 72.1 ± 2.56 ± 505 ±

1.2 4.1 0.12 93

Placebo 20)

p

39.6 ± 1.4 73.2 ± 4.2 2.75 ± 0.15 426 ± 43

NSb NS NS NS

(n =

a Mean b

± standard error. NS, not significant.

In group B, all20 patients finished 12 weeks of placebo injections, and 17 patients completed the 24week study. Three women discontinued the treatment protocol because each had persistent menorrhagia, their primary presenting symptom. Figure 1 illustrates the mean uterine volumes, as calculated by ultrasonic measurements, before therapy, and at 12 and 24 weeks in both treatment groups, and at 3 months of follow-up in leuprolidetreated patients. In group A, the mean pretreatment uterine volume of 505 ± 93 cu em decreased significantly to 305 ± 57 cu em at 12 weeks (P < 0.05 versus pretreatment) with no further uterine shrinkage at 24 weeks (307 ±57 cu em, P < 0.05 versus pretreatment). At 12 and 24 weeks of leuprolide therapy, 3 of 18 patients (17%) had 15 to 25% reduction in uterine volume, eleven of 18 patients (61%) experienced 25 to 50% reduction, and 4 of 18 (22%) had >50% reduction in uterine volume. Mean uterine volume for group A patients increased to 446 ± 92 cu em (P = not significant versus pretreatment) within 3 months after cessation of therapy. In group B, uterine volume did not change significantly from pretreatment to 12 or 24 weeks of treatment (426 ± 43 cu em, 438 ± 45 cu em, and 429 ±52 cu em, respectively).

Total cholesterol (mg/dl) LDL-cholesterol (mg/dl) HDL-cholesterol (mg/dl) Cholesterol/ HDLratio

Treatment week

Leuprolide (n = 16)

0 24 0 24 0 24 0 24

203±9 219 ± 11b 127±8 139 ± 11 59±3 54±3· 3.67 ± 0.31 4.27 ±0.39d

Placebo 17)

(n =

212±9 211 ± 10 123 ±7 130±8 58±4 56±4 3.87 ± 0.26 3.82 ±0.22

a Mean±

standard error. P < 0.05 compared with week 0. • P < 0.01 compared with week 0. d P < 0.0005 compared with week 0. b

Figure 1 Changes in mean uterine volume during depot leuprolide and placebo therapy.

In group A, mean E 2 levels fell from a pretreatment midluteal phase concentration of 150 ± 12 pg/ml to 16 ± 3 pg/ml at 12 weeks (P < 0.0001) and 27 ± 9 pg/ml at 24 weeks (P < 0.0001). Mean E 2 concentrations did not change significantly in group B (133 ± 17 pg/ml, 86 ± 14 pg/ml, and 144 ± 29 pg/ml at 0, 12 and 24 weeks of treatment, respectively). Before treatment, mean serum LH levels were 8.4 ± 2.0 miU/ml for patients in group A and 7.6 ± 2.1 miU/ml in group B patients. Mean FSH levels were 4.9 ± 1. 7 miU/ml in group A patients and 5.6 ± 1.2 miU/ml for patients in group B. There were no within- or between-group differences in gonadotropin concentrations at 0, 12, and 24 weeks of treatment. The mean pretreatment midluteal P concentration was 10.2 ± 1.8 ng/ml in group A, with each patient having a level > 4 ng/ml. Progesterone concentrations were <1.5 ng/ml for each patient in group A at 12 and 24 weeks of therapy. The mean pretreatment P concentration was 11.2 ± 2.1 ng/ml in group B and was 3. 7 ± 2.8 pg/ml at 12 weeks and 3.8 ± 3.0 ng/ml at 24 weeks. Fasting lipid profiles obtained before and after 24 weeks of therapy are shown for both groups in Table 2. In group A, total cholesterol increased from 203 ± 9 mg/dl to 219 ± 11 mg/dl (P < 0.05), HDL-cholesterol decreased from 59± 3 mg/dl to 54± 3 mg/dl (P < 0.01), andcholesterol/HDL-cholesterol ratios increased significantly from 3.67 ± 0.31 to 4.27 ± 0.39 (P < 0.0005) over the 24-week period. Fasting LDL-cholesterol concentrations showed no significant change from pretreatment to week 24 in group A patients. Lipid levels in group B patients showed no significant changes during the 24-week treatment period. Serum chemistries are reported for both groups

Vol. 51, No.2, February 1989

Friedman et al.

Uterine Volume (om3)

eoo r - - . . - - - - - - - - - - - - - - , , - - - - - - - , 400

II Depot Leuprollde •

Pretr. .tment

12 Treatment Week

24

Placebo

•p<0.05 v1. Pretreatment

Leuprolide depot therapy for fibroids

253

Table 3 Serum Chemistries During Leuprolide and Placebo Treatment•

Alkaline phosphatase (U/1)

SGOT (U/1)

SGPT (U/1)

LDH (U/1)

Calcium (mg/dl) Phosphate (mg/dl) Albumin (g/dl)

Treatment week

Leuprolide (n = 16)

Placebo (n = 17)

0 24 0 24 0 24 0 24 0 24 0 24 0 24

65±5 86±8b 21 ± 1 24±2· 19± 2 26±3d 174±6 190 ± 8d 9.3±0.1 9.7 ± 0.1" 3.3 ± 0.1 3.9±0.1b 4.1 ± 0.1 4.3 ± 0.1"

71±5 75±5 29±4 22±2d 26±3 19±3 161 ±5 168±8 9.4±0.1 9.3±0.1 3.3 ± 0.1 3.4 ±0.1 4.0±0.1 4.1 ± 0.1

• Mean ± standard error. b p < 0.0001 compared with week 0. • P < 0.05 compared with week 0. d P = 0.07 compared with week 0. • P < 0.005 compared with week 0.

in Table 3. Significant increases from pretreatment to week 24 were noted for alkaline phosphatase, serum aspartate aminotransferase (SGOT), calcium, phosphate, and albumin in the depot leuprolidetreated group. There were no significant changes noted in group B for these chemistry values. There were no significant changes in hemoglobin concentrations or hematocrits in either group by 24 weeks of treatment compared with baseline values. In group A, the mean pretreatment hemoglobin level was 12.3 ± 0.4 gm/dl and 13.0 ± 0.3 gm/ d1 after 24 weeks. The mean hematocrit was 36.3 ± 1.0% before treatment, and 38.1 ± 0.9% after 24 weeks in group A patients. In group B, the mean hemoglobin concentration was 12.3 ± 0.3 gm/dl before treatment and 11.3 ± 0.6 gm/dl after 24 weeks. The mean hematocrit was 36.3 ± 0.8% before therapy and 33.9 ± 1.6% after 24 weeks of treatment in group B patients. Ultradistal bone density did not change significantly by 24 weeks of treatment in either group. In group A, the mean pretreatment density was 0.35 ± 0.02 gm/sq em compared with 0.34 ± 0.02 gmjsq em at 24 weeks. In group B, ultradistal bone density was 0.36 ± 0.01 gm/sq em before treatment and 0.36 ± 0.01 gm/sq em after 24 weeks. Adverse symptoms experienced by patients treated with leuprolide depot are recorded in Table 4. The most commonly encountered side effect was hot flashes, which were noted in all 18 women treated with depot leuprolide. Two patients in this group discontinued treatment after 12 weeks be254

Friedman et al. Leuprolide depot therapy for {ibroids

cause hot flashes were severe. Hot flashes and other adverse symptoms were well tolerated by the remaining 16 patients. In patients treated with placebo, 3 patients experienced hot flashes. No other new symptoms occurred in this latter group during the 24-week treatment period. All patients treated with placebo continued to have regular menses during the treatment period. In the group of patients treated with leuprolide depot, 12 of 18 were amenorrheic by 4 weeks, and the remaining 6 patients experienced intermittent and irregular vaginal bleeding throughout the treatment protocol. Return of menses occurred on average 71 ± 11 days (range, 35 to 211 days) after the last leuprolide depot injection. All patients except 1 in group A experienced menses within 85 days after their last injection. The patient who did not have menses until 211 days after her final injection lost 20 kg, from 80 kg to 60 kg, on a voluntary diet that began after 4 months of leuprolide depot treatment and continued throughout the 6-month follow-up period. DISCUSSION

In this placebo-controlled, double-blinded randomized study, no change in uterine volume was found after 24 weeks of treatment in placebotreated patients. Treatment with leuprolide acetate depot caused a mean reduction in uterine volume of 40%. The observed decrease in uterine size is comparable to that reported in earlier studies. 4-a Maximal reduction in uterine volume was achieved by 12 weeks of therapy, with no further change observed after 24 weeks of treatment. However, mean uterine volume increased to 88% of pretreatment Table 4

Adverse Symptoms During Leuprolide Treatment Symptom

Number

Hot flashes Irregular vaginal bleeding Peripheral edema Insomnia Depression Joint pain Headaches Fatigue Vaginal dryness Increased appetite Increased thirst Uterine cramping Vaginal discharge

18/18 (100) 6/18 (33) 5/18 (28) 4/18 (22) 4/18 (22) 4/18 (22) 4/18 (22) 2/18 (11) 2/18 (11) 1/18 (6) 1/18 (6) 1/18 (6) 1/18 (6)

%

Fertility and Sterility

size within 3 months of cessation of leuprolide therapy in 16 patients who completed 3 months of follow-up. The rapid regrowth of leiomyomata uteri soon after termination of depot leuprolide injections suggests that primary medical therapy with a GnRHa alone is unlikely to permanently eradicate symptoms due to leiomyomata. Rather, leuprolide may be useful as a preoperative adjuvant for hysterectomy and myomectomy. By decreasing uterine size, it might be possible in selected cases to perform hysterectomies through the vaginal route, an approach that carries half the morbidity compared with abdominal hysterectomy. 10 In addition, in a case where only abdominal hysterectomy is possible, a smaller uterus may allow the surgeon to use a Pfannenstiel incision, which is stronger than a midline vertical incision. Preoperative treatment of leiomyomata uteri with a GnRHa may decrease intraoperative blood loss at hysterectomy. 8 Finally, shrinkage of a fibroid uterus may facilitate localization and division of vascular pedicles and visualization of the pelvic ureter, potentially decreasing operative morbidity. Treatment with leuprolide acetate was associated with changes in some serum chemistry values. Total fasting cholesterol increased and HDL-cholesterol decreased over the 24-week treatment period in leuprolide-treated patients. The magnitude of these changes was small, with mean values remaining within normal ranges, and it is therefore unclear whether lipid alterations seen after leuprotide therapy have biologic significance. The changes in lipid profiles observed in this study are similar to those previously reported in postmenopausal women. Total serum cholesterol has been shown to increase after natural or surgical menopause.11·12 In addition, N otelovitz et al. 12 have found lower levels of HDL-cholesterol in young oophorectomized women when compared with agematched controls. Many investigators have hypothesized that hypoestrogenemia is responsible for changes in lipid profiles observed in postmenopausal women. Small increases in mean serum concentrations of alkaline phosphatase and SGOT were noted over the 24-week study period in patients treated with leuprolide. Increases in these enzymes have been reported previously in patients treated with other GnRHa. 13·14 Serum calcium and phosphate concentrations increased significantly in leuprolidetreated patients over the 24-week protocol. The increase observed for calcium was not significant Vol. 51, No.2, February 1989

when corrected for the rise in serum albumin concentrations. The increase observed in mean serum phosphate concentration has not been reported previously in patients treated with GnRHa. The mechanisms by which calcium, albumin, phosphate, SGOT, and alkaline phosphatase increase during leuprolide therapy are unknown and require further study. In this study, as in others,5 •6 no changes were observed in bone density measurements of the ultradistal radius as measured by single photon absorptiometry over 24 weeks in leuprolide-treated patients. More sensitive measurements of small changes in trabecular bone density would be possible with dual photon absorptiometry, dual photon xray, or computerized tomography. In summary, depot LA was successful in significantly decreasing uterine volume in premenopausal women with leiomyomata uteri. The depot delivery system had high patient acceptance. The reduction in uterine size is transient, as evidenced by a rapid growth phase following cessation of therapy. Thus, LA may be useful in selected preoperative patients scheduled to undergo hysterectomy or myomectomy. The decrease in uterine volume may make surgery technically easier with less blood loss in some patients. Further studies are necessary to evaluate leuprolide as a preoperative adjuvant and to assess its safety in long-term use.

Acknowledgments. We acknowledge Takeda-Abbott Research and Development for providing leuprolide acetate depot and placebo formulations, Ms. Victoria Vallee for assistance in data analysis, Ms. Marie Francis, C.N.M.T., for performance of all single-photon bone densitometries, and Ms. Robin Craig for preparation of this manuscript.

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