Efficacy of a low-dose leuprolide acetate depot in the treatment of uterine leiomyomata in Japanese women*

"

Vol. 58, No.1, July 1992

FERTILITY AND STERILITY Copyright

©

Printed on acid·free paper in U.S.A.

1992 The American Fertility Society

Efficacy of a low-dose leuprolide acetate depot in the treatment of uterine leiomyomata in Japanese women*

Yoshitsugu Watanabe, M.D.t Gen-ichi Nakamura, M.D. Hiroshi Matsuguchi, M.D.

Masahiro Nozaki, M.D. Masatoshi Sano, M.D. Hitoo Nakano, M.D.

Department of Gynecology and Obstetrics, Faculty of Medicine, Kyushu University, Fukuoka, Japan

Objective: To compare the efficacy of two different doses, 1.88 mg and 3.75 mg, of a monthly depot injection of a gonadotropin-releasing hormone agonist (GnRH-a) in the treatment of uterine leiomyomata. Design: A prospective randomized study. Setting: Hospital department of gynecology and obstetrics. Patients: Forty-one premenopausal Japanese women, 25 to 53 years of age, with uterine leiomyomata. Interventions: Depot type of GnRH-a, leuprolide acetate (LA) 1.88 mg or 3.75 mg was administered subcutaneously every 4 weeks for 24 weeks. Main Outcome Measures: Efficacy of treatment was assessed in terms of uterine volume, serum levels of estradiol (E 2 ), luteinizing hormone (LH), follicle-stimulating hormone (FSH), and adverse symptoms during treatment. Results: In both groups, a significant reduction in uterine volume, 52% in 1.88 mg group and 47% in 3.75 mg group, was obtained at week 24, with near maximal reduction (41 %, 45%) apparent by 12 weeks. No significant difference was observed between the groups in percent uterine volume reduction at each treatment week. Both groups showed significant and equal suppression of serum levels of E 2 , LH, and FSH. In addition, the incidence of adverse symptoms was not significantly different between the two groups. Conclusions: Monthly injection of 1.88 mg or 3.75 mg LA depot has equivalent treatment efficacy in reducing uterine volume. Twelve weeks of treatment is enough to obtain near maximal reduction. Fertil Steril 1992;58:66-71 Key Words: Gonadotropin -releasing hormone agonist, leuprolide depot, uterine leiomyoma, dose dependency

Gonadotropin -releasing hormone agonists (GnRH-a) have been successfully used to decrease uterine and leiomyoma volume. Many studies have demonstrated that administration of GnRH-a, through intranasal spray or subcutaneous (SC) in-

Received September 3, 1991; revised and accepted March 10, 1992. * Supported in part by the Japan Ministry of Health and Welfare in aid for "Reproductive Health Research," Tokyo, Japan. t Reprint requests: Yoshitsugu Watanabe, M.D., Department of Gynecology and Obstetrics, Faculty of Medicine, Kyushu University, 60, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812, Japan.

66

Watanabe et al.

LA depot for uterine leiomyomata

jection, induces a hypoestrogenic state and reduces the uterine size (1-13). This study describes the use of a monthly depot injection of leuprolide acetate (LA). Although some studies (11-13) have demonstrated that administration of LA depot, 3.75 mg for 4 to 6 months, causes a reduction in uterine volume by 34 % to 40%, the ideal therapeutic dose has not been identified. The object of the present study was to evaluate the effect of two different doses, 1.88 mg and 3.75 mg, of LA depot and compare their efficacy in the treatment of uterine leiomyomata. The present study also gave us an opportunity to observe the efficacy of LA depot in Asian women.

Fertility and Sterility

MATERIALS AND METHODS Patient Population

Forty-one premenopausal women, 25 to 53 years of age, with uterine leiomyomata presenting as an enlarged uterus, hypermenorrhea, dysmenorrhea, and/or infertility participated in this study. Informed consent was obtained from all patients after the therapeutic options had been explained. They complained of the following symptoms: hypermenorrhea (83%), dysmenorrhea (22%), and urinary frequency (15%). Eighteen patients (44%) were found to have anemia (hemoglobin < 11 g/dL). Eleven patients wished to maintain their reproductive capacity. All patients had histories of regular menstrual cycles before the study and showed no signs of uterine neoplasia on cervical and endometrial smear or biopsy. Treatment Protocol

Subjects were randomized by random sampling number to receive 2 mL of microcapsule suspension containing LA depot (D-Leu6 -[des-Glylo-NH 2]-luteinizing hormone[LH]-releasing hormone ethylamide acetate sustained release; Takeda Chemical Industries Co. Ltd., Osaka, Japan) 1.88 mg (group A, n = 20) or 3.75 mg (group B, n = 21) SC every 4 weeks for 24 weeks into the lateral abdominal wall. Treatment was initiated on the 1st to 3rd day of the menstrual cycle. Patients were seen at 4-week intervals during the treatment period and at 3 and 6 months after cessation oftherapy. During each visit, patients underwent a gynecological examination and a pelvic ultrasound examination using a real-time sector scanner to assess uterine and leiomyoma size. The subjects were questioned about the occurrence of vaginal bleeding, pelvic pain, and adverse symptoms attributable to therapy: the occurrence and frequency of hot flushes, shoulder stiffness, headache, insomnia, joint pain, paresthesia of hand, induration of injection site, vertigo, dizziness, breast pain, and fatigue. In addition, serum levels of estradiol (E 2), LH, and follicle-stimulating hormone (FSH) were tested. The patients were instructed to record basal body temperature (BBT) charts during and after treatment to confirm the suppression and recovery of ovulation. Hormonal Assays

Serum levels of E 2, LH, and FSH were measured by radioimmunoassay technique. Serum levels of E2

Vol. 58, No.1, July 1992

were assayed with Coat-A-Count Estradiol (Diagnostic Products Corporation, Los Angeles, CA). Serum levels of LH and FSH were assayed with Spac-S-LH or -FSH kits (Daiichi Radioisotope Co. Ltd., Tokyo, Japan). The intra-assay and interassay coefficients of variation (CVs) were 3.4% and 4.6% for E 2, 2.7% and 4.3% for LH, and 2.2% and 3.0% for FSH. Ultrasound Technique

Serial measurements of the uterus and any identifiable leiomyoma were performed in the three largest dimensions, and a prolate ellipse equation was used to calculate the volume (14). All measurements were performed by the same examiner (G.N.). A realtime ultrasonography scanner (model SAL-38A; Toshiba, Tokyo, Japan) with a 3.5-MHz linear transducer was used to determine uterine and leiomyomata dimensions. The intra-assay and interassay CVs were 5.0% and 5.9%, respectively. Statistical Analyses

All data are presented as the mean ± SD. Data were analyzed using a paired t-test for within-group and an unpaired t-test for between-groups differences. The X2 test was used to analyze the incidence of adverse symptoms. A P value of <0.05 was considered significant. RESULTS Patient Profile

Demographic data for both groups of patients are reported in Table 1. Randomization resulted in the groups being well matched for age, weight, height, history of conception, site of leiomyomata, and pretreatment uterine volume. No significant differences were found between the groups for each of these parameters. The rates of incidence of presenting symptoms in groups A and B were 80% and 86% for hypermenorrhea, 15% and 38% for dysmenorrhea, 15% and 14% for urinary frequency, and 55% and 33 % for anemia. Uterine Volume During GnRH-a Therapy

Mean uterine volume decreased in group A (1.88 mg) from 553 ± 499 cm3 (173 cm3 to 2,382 cm3 ) to 295 ± 351 cm3 (63 cm3 to 1,447 cm3 ) after 24 weeks of treatment, for an average decrease of 51.5%. In

Watanabe et al.

LA depot for uterine leiomyomata

67

Table 1

Demographic Data

be followed up for their uterine size after stopping treatment. Both groups showed the same regrowth rate at 3 and 6 months after cessation of therapy.

LA depot 1.88 mg = 20)

(n

Age (y) Weight (kg) Height (cm) History of conception Site of leiomyomata Intramuralis Subserosum Submucosum Pretreatment uterine volume (cm a )

42.2 54.5 155.3 13

± 7.0* ± 9.4 ± 4.1 (65)+

18 (90)

3.75 mg = 21)

(n

42.0 ± 6.5t 52.9 ± 8.6t 154.9 ± 4.0t 16 (76)t

2 (10)

19 (90)t 4 (19)t

2 (10)

1 (5)t

553 ± 499

452 ± 224t

* Values are means ± SD. t Not significant compared with 1.88 mg.

+Values are the number of patients and in parentheses the

Hormonal Concentrations

Pretreatment serum E2 concentrations obtained in the early follicular phase ofthe cycle immediately preceding the initiation of therapy were 54.5 ± 43.8 pg/mL in group A and 69.5 ± 65.7 pg/mL in group B, which are normal levels for premenopausal women. After 4 weeks of therapy, significant decreases to levels of postmenopausal women «30 pg/mL), 19.8 ± 18.1 pg/mL in group A and 19.0 ± 8.3 pg/mL in group B, were observed. Mean E2 levels remained below 30 pg/mL during the remain-

percentage of the group.

o group B (3.75 mg), the mean pretreatment uterine volume was 452 ± 224 cm3 (148 cm3 to 1,483 cm3 ) compared with 271 ± 314 cm3 (55 cm3 to 1,196 cm3 ) at week 24, representing an average decrease of 47.4%. The serial percent reduction in uterine volume is shown in Figure 1A. A significant percent reduction was observed by 4 weeks in both groups: 29% in group A and 27% in group B. In both groups, uterine volume continued to decrease until 12 weeks, by 41 % in group A and by 45% in group B. Minimal further reduction in uterine size was observed thereafter for the duration of therapy. The percent reduction at 24 weeks was 52% in group A and 47% in group B. The chronological percent reduction in uterine volume between the groups was not statistically significant. The percent reduction of leiomyomata volume at each week showed the same pattern as the uterine volume (Fig. 1B), although only 9 of 20 in group A and 7 of 21 in group B could be measured because the contours of the leiomyomata became unclear during treatment. The percent reduction of leiomyomata volume in group A and group B were 37% and 24% at 4 weeks, 51 % and 56% at 12 weeks, and 54% and 43% at 24 weeks, respectively. The size of the leiomyomata also decreased significantly in both groups. Again, no statistically significant difference was observed between the two groups. Uterine and leiomyomata volume returned to pretreatment values 6 months after cessation of therapy (data not shown). Because most of the study subjects underwent hysterectomy or myomectomy, only 6 of 20 in group A and 3 of 21 in group B could

68

Watanabe et a1.

LA depot for uterine leiomyomata

A

• 50

100L---,----r--~--~~--r_--~--_r_

o

4

8

12

16

20

24

Weeks

~

.,

o

B

E :::l

(3

>

2l(tJ E

•

g.

E

o ~

•

50

....o 2l (tJ

...

c:: o .;:;

"

:::l

-c CD

II:

100L---~---r--~--~----r_--~--_r_

o + depot + +Weeks + + acetate + Leuprolide 4

8

12

16

20

24

Figure 1 Percent reduction in uterine and leiomyomata volume determined sonographically during LA depot therapy compared with pretreatment. (A), Uterine volume, • 1.88 mg of LA depot (n = 20); 0 3.75 mg of LA depot (n = 21). (B), Leiomyomata volume, • 1.88 mg of LA depot (n = 9); 0 3.75 mg of LA depot (n = 7). *P < 0.01 versus pretreatment. Data are means ± SD.

Fertility and Sterility

der of the treatment period in both groups (Fig. 2A). There were no significant differences in E2 level between the groups at each treatment week. Serum LH concentrations, which were initially found to be within the normal range for premenopausal women, 8.2 ± 9.6 mIU/mL in group A and 7.2 ± 6.9 mIU/mL in group B, were suppressed to values < 1 mIU/mL as early as 4 weeks after beginning treatment, and these reduced values of LH continued for the duration of therapy. Mean serum FSH levels decreased from 19.8 ± 15.3 mIU /mL in group A and 18.6 ± 18.4 mIU /mL in group B before treatment to 5.4 ± 2.9 mIU /mL and 4.2 ± 2.7 mIU/mL at week 4, respectively. The mean FSH levels before treatment were high for the early follicular phase because several perimenopausal women showed high serum FSH concentrations in spite of their regular menstrual cycles. Reduced concentrations of FSH were observed throughout the 24 weeks of therapy. Neither gonadotropin concentration showed any significant difference at any treatment week between the groups (Fig. 2B and C).

80 A

60

:J' E

}

40

w'" 20

O~--~--~--~---r--~--~--~4 8 12 16 20 24 o

Weeks

15

:J' .....E

B

10

~

E

'-'

=s

5

Clinical Responses

All patients in both groups experienced partial or complete relief from symptoms throughout the therapy. Four patients in each group had intermittent or irregular vaginal spotting throughout the treatment protocol. Two of the 20 patients treated with 1.88 mg of LA depot experienced menstruationlike vaginal bleeding at 4 weeks of therapy. On the other hand, all the patients treated with 3.75 mg of LA depot were amenorrheic after 4 weeks of treatment. Basal body temperature charts revealed no ovulation in all the patients of both groups during the treatment. Return of ovulation occurred, on average, 69.8 ± 24.0 days from the last injection of LA depot in group A versus 78.1 ± 20.2 days in group B, which was not significantly different.

o 30

4

8

**

**

**

**

12

16

20

24 Weeks

C

:J'

~

~

20

E

'-'

::c ~

10

O~--~--~--~--~--~--~--~4 12 20 24 8 16

o

+ + acetate + Leuprolide + depot + + Weeks

Figure 2 Serum concentration of E2 (A), LH (B), and FSH (C) during LA depot therapy expressed as means ± SD. 1.88 mg of LA depot (e); 3.75 mg of LA depot (O).*P < 0.01 versus pretreatment.

Adverse Symptoms

Adverse symptoms experienced by the patients are recorded in Table 2. No significant difference was found between the groups for each of these adverse effects. The most commonly encountered adverse effect was hot flushes, experienced by all women in group A and 16 of 21 women in group B. One patient in group A discontinued treatment after 12 weeks because of severe lumbago. In group B, one patient dropped out of the treatment protocol after

Vol. 58, No.1, July 1992

8 weeks because of severe joint pain and back pain. Hot flushes and other adverse symptoms were well tolerated by the remaining patients. All symptoms resolved in all patients within 4 weeks after the cessation of therapy. DISCUSSION

The use of the depot type of GnRH -a for the treatment of uterine leiomyomata has been suc-

Watanabe et al.

LA depot for uterine leiomyomata

69

, Table 2

Adverse Symptoms During Treatment LA depot

Hot flushes Shoulder stiffness Headache Insomnia Joint pain Paresthesia of hand Induration of injection site Vertigo, dizziness Breast pain Fatigue

1.88 mg

3.75 mg

(n = 20)

(n = 21)

20 12 10 4 3

(100)* (60) (50) (20) (15)

1 (5) 1 (5)

3 (15) 0(0) 1 (5)

16 12 8 6 3 3 3

(76)t (57)t (38lt (29)t (14lt (14lt (14lt o (Olt 2 (lO)t

o (O)t

* Values in parentheses are percents. t Not significant compared with 1.88 mg.

cessful both in reducing uterine and leiomyomata volumes and in inducing amenorrhea. Several recent reports (6, 7, 11-13) have demonstrated reductions in uterine and leiomyomata volume by 34% to 55% after 4 to 6 months of monthly depot injections of GnRH-a. In this study, patients were treated for 24 weeks with monthly injections of 1.88 mg or 3.75 mg of LA depot, and the efficacy of the two doses was compared. The observed decrease in uterine size at both doses is significant and comparable with that reported in earlier studies (6, 7, 11-13), indicating that this agent is equally effective in Japanese women. Uterine volume decreased, on average, by 52% in 1.88 mg group and by 47% in 3.75 mg group, compared with pretreatment size. There was no significant difference between the two groups. Both groups showed significant suppression of the serum levels of E 2 , LH, and FSH. No significant difference was found between the groups. In addition, no significant difference was observed between the two groups in time to recovery of ovarian function, relief from symptoms, and incidence of adverse symptoms. The role of GnRH -a in the clinical management of leiomyoma uteri is still being defined. In the present study, uterine and leiomyomata volume returned to pretreatment values 6 months after cessation of therapy. Follow-up data were quite limited, with only 9 of 41 patients available 6 months after therapy because the majority of patients enrolled in the trial underwent surgical treatment. Several studies have reported that most leiomyoma returned to near pretreatment size after cessation of GnRH -a therapy (5, 7, 11, 13); it is likely that this therapy provides a temporary method of management and not defin-

70

Watanabe et al.

LA depot for uterine leiomyomata

itive treatment. These agonists may be useful either as a preoperative adjuvant therapy to make the operation easier and minimize complication rates by reducing leiomyomata size or in perimenopausal women with leiomyomata to avoid operative therapy by producing adequate resolution of symptoms until natural menopause occurs (6, 12). It is important to know how long the GnRH-a administration should be continued and which amount should be used to obtain the best therapeutic response. A greater reduction in the volume of the uterus and leyomyomata was observed during the first 4 weeks of treatment, and minimal reduction was seen after 12 weeks in our study and in others (7, 11), which suggests that 12 weeks of treatment is enough to obtain near maximal results. Because the administration of 1.88 mg and 3.75 mg of LA depot showed an equivalent effect in hormonal suppression, reduction of uterine size and incidence of adverse symptoms, it appears that these two doses are within the therapeutic range and that the lower dose is preferable. A reasonable future objective will be to determine the ideal therapeutic dose that gives positive therapeutic effects with minimal adverse effects. Is it possible that women with lower body weight have a greater reduction in uterine volume, regardless of dose? If the plasma levels of GnRH-a are inversely related to body weight, treatment efficacy may vary with body weight. Further studies on correlation body weight with E2 levels and the reduction in uterine volume are needed to determine the optimal therapeutic dose. Acknowledgment. We thank Takeda Chemical Industries Co. Ltd. (Osaka, Japan) for providing LA depot and for assistance in data analysis.

REFERENCES 1. Filicori M, Hall DA, Loughlin JS, Rivier J, Vale W, Crowley WF. A conservative approach to the management of uterine leiomyoma: pituitary desensitization by a luteinizing hormone-releasing hormone analogue. Am J Obstet Gynecol 1983;147:726-7. 2. Maheux R, Guilloteau C, Lemay A, Bastide A, Fazekas AlA. Luteinizing hormone-releasing hormone agonist and uterine leiomyoma: a pilot study. Am J Obstet Gynecol 1985;152: 1034-8. 3. Coddington CC, Collins RL, Shawker TH, Anderson R, Loriaux DL, Winkel CA. Long-acting gonadotropin hormonereleasing hormone analog used to treat uteri. Fertil Steril 1986;45:624-9. 4. Healy DL, Lawson SR, Abbott M, Baird DT, Fraser HM. Toward removing uterine fibroids without surgery: subcu-

Fertility and Sterility

5.

6. 7.

8.

9.

taneous infusion of a luteinizing hormone-releasing hormone agonist commencing in the luteal phase. J Clin Endocrinol Metab 1986;63:619-25. Friedman AJ, Barbieri RL, Benacerraf BR, Schiff I. Treatment of leiomyomata with intranasal or subcutaneous leuprolide, a gonadotropin-releasing hormone agonist. Fertil Steri 1987;48:560-4. Lumsden MA, West CP, Baird DT. Goserelin therapy before surgery for uterine fibroids. Lancet 1987;1:36-7. West CP, Lumsden MA, Lawson S, Williamson J, Baired DT. Shrinkage of uterine fibroids during therapy with gosere lin (Zoladex): a luteinizing hormone-releasing hormone agonist administered as a monthly subcutaneous depot. Fertil Steril 1987;48:45-51. Andreyko JL, Blumenfeld Z, Marshall LA, Monroe SE, Hricak H, Jaffe RB. Use of an agonist analog of gonadotropinreleasing hormone (Nafarelin) to treat leiomyomas: assessment by magnetic resonance imaging. Am J Obstet Gynecol 1988;158:903-10. Benagiano G, Primiero F, Morini A, Isidori C, Addi G, Tunner G. Multimodal pharmacological approach to the treatment of leiomyomata uteri. Gynecol Endocrinol 1988;2(2 Suppi):50.

Vol. 58, No.1, July 1992

10. Matta WHM, Stabile I, Shaw RW, Campbell S. Doppler assessment of uterine blood flow changes in patients with fibroids receiving the gonadotropin -releasing hormone agonist buserelin. Fertil Steril1988;49:1083-5. 11. Friedman AJ, Harrison-Atlas D, Barbieri RL, BenacerrafB, Gleason R, Schiff I. A randomized, placebo-controlled, doubleblind study evaluating the efficacy of leuprolide acetate depot in the treatment of uterine leiomyomata. Fertil Steril 1989;51: 251-6. 12. Friedman AJ, Rein MS, Harrison-Atlas D, Garfield JM, Doubilet PM. A randomized, placebo-controlled, double-blind study evaluating leuprolide acetate depot treatment before myomectomy. Fertil Steril 1989;52:728-33. 13. Schlaff WD, Zerhouni EA, Huth JAM, Chen J, Damewood MD, Rock JA. A placebo-controlled trial of depot gonadotropin-releasing hormone analogue (leuprolide) in the treatment of uterine leiomyomata. Obstet Gynecol 1989;74: 856-62. 14. Shawker TH. Monitoring response to therapy. In: Brascho DJ, Shawker TH, editors. Abdominal ultrasound in the cancer patient. New York: John Wiley and Sons, 1980:113-34.

Watanabe et al.

LA depot for uterine leiomyomata

71