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Predictors of uterine volume reduction in women with myomas treated with a gonadotropin-releasing hormone agonist*
FERTILITY AND STERILITY
Vol. 58, No.2, August 1992
Copyright © 1992 The American Fertility Society
Printed on acid-free paper in U.S.A.
Predictors of uterine volume reduction in women with myomas treated with a gonadotropin-releasing hormone agonist*
Andrew J. Friedman, M.D.t Margaret Daly, R.N. Mary Juneau-Norcross, R.N. Mitchell S. Rein, M.D. Department of Obstetrics and Gynecology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts
Gonadotropin-releasing hormone agonists (GnRH-a) are commonly used to induce uterine shrinkage and menstrual suppression for both temporary relief of myoma-related symptoms and as a preoperative treatment before myomectomy or hysterectomy. Although mean uterine volume reduction has reportedly ranged from 40% to 50%, significant variability in uterine volume changes has been reported (1-4). Uterine volume has been reported to decrease as much as 80% in some cases, whereas no reduction or an actual increase in uterine size has occurred in others. The ability to predict those women who would be expected to exhibit significant reductions in uterine volume would have great potential utility, especially in women receiving GnRH-a in preparation for uterine surgery. In this study, several variables were evaluated as predictors of uterine volume reduction in 104 women with myomas who received the GnRH-a, leuprolide acetate (LA), for at least 12 weeks. MATERIALS AND METHODS
One hundred four premenopausal women with leiomyomata uteri received LA for at least 12 weeks. The results of LA treatment in many of these women have been reported in previous studies (1-4). Received February 10, 1992; revised and accepted. April 6, 1992.
* Supported in part by grant 7-M01-RR 02635-01 from the General Clinical Research Center, Brigham and Women's Hospital, Boston, Massachusetts. t Reprint requests: Andrew J. Friedman, M.D., Department of Obstetrics and Gynecology, Brigham and Women's Hospital, 75 Francis Street ASBI-2-104, Boston, Massachusetts 02115. Vol. 58, No.2, August 1992
Twenty-three women received LA, 0.5 mg/d subcutaneously, and 81 women received LA depot 3.75 mg intramuscularly every 28 days beginning anytime between the midluteal (i.e., cycle day 21) and early follicular phases (i.e., cycle day 3). In each woman, the uterus was measured in three dimensions (i.e., anteroposterior, length, width) with an Acuson 128 phased array variable focus system (Acuson, Inc., Mountview, CA) with a 3.5-MHz transducer before treatment and after receiving LA for 12 weeks. Uterine volume was calculated as an ellipsoid by the formula (0.524)(D 1)(D2)(D a) where Db D2, and Da were the diameters of the three measured uterine dimensions. Serum estradiol (E 2) was assayed using a direct 125I_E2 radioimmunoassay kit (Pantex, Santa Monica, CA) with a sensitivity of 4 pg/mL and intra-assay and interassay variations of 2.1 % and 4.6%, respectively. Data collected for each woman included age, height, weight, pretreatment uterine volume, pretreatment E2 concentrations in the midluteal phase, uterine volume at 12 weeks of treatment, and week 12 serum E2 concentrations. An unpaired t-test was used to test whether there was a significant difference in the decrease in mean uterine volume at 12 weeks between women with week 12 serum E2 concentrations ;5; 30 pg/mL and women with E2 levels > 30 pg/mL. Relationships between percent decrement in uterine volume at week 12 and other variables were tested for dependence using standard Pearson's product-moment correlations. RESULTS
The mean age of women in this study was 41.4
± 0.7 years (mean ± SE; range, 28 to 53 years), with Friedman et al.
Communications-in-brief
413
a mean height of 163.2 ± 0.7 cm (range 149 to 1,833 cm) and a mean weight of 68.9 ± 2.0 kg (range 41 to 166 kg). Mean pretreatment uterine volume was 727 ± 53 cm3 (range 96 to 2,810 cm3 ) and the mean week 12 uterine volume was 464 ± 40 cm3 (range 73 to 1,751 cm3 ). The mean decrease in uterine volume was 36.2% ± 2.0%, with a maximum decrease in uterine volume of 73.6% and a maximum increase in uterine volume of 24.3 %. Patients were also analyzed for degree of uterine size change. Four of 104 women (3.8%) had increases in uterine volume from 0.1 % to 25% by treatment week 12, 25 women (24.0%) had decreases in uterine volume from 0.1 % to 25%, 53 women (51.0%) had decreases in uterine volume from 25.1% to 50%, and 22 women (21.2%) had decreases in uterine volume> 50%. The mean pretreatment E2 concentration obtained in the midluteal phase was 122 ± 11.7 pgjml (range 68 to 227 pgjmL). At week 12, the mean E2 concentration was 24.3 ± 2.8 pgjmL (range 4 to 168 pgjmL). No significant correlation was noted between change in uterine volume at week 12 and the following variables: age, height, and pretreatment uterine volume. A significant negative correlation was noted between percent decrease in uterine volume at 12 weeks of treatment and week 12 serum E2 concentrations (r = -0.237, P = 0.03). The mean decrease in uterine volume for all women with week 12 serum E2 concentrations:::; 30 pgjmL was 43.1% ± 3.3% (range 12.0% to 73.6% decrease); in contrast, the mean decrease in uterine volume for all women with week 12 serum E2 concentrations> 30 pgjmL was 18.2% ± 5.3% (range 24.3% increase to 47.1 % decrease) (P < 0.01). Weight was also negatively correlated with the percent decrease in uterine volume (r = -0.513, P < 0.001, Fig. 1); however, weight was not correlated with serum E2 concentrations at 12 weeks of LA therapy (r = 0.014, P = 0.90). DISCUSSION
In this retrospective analysis of 104 women with myomas undergoing treatment with LA for at least 12 weeks, the percent decrease in uterine volume was found to correlate negatively with both serum E2 concentration at treatment week 12 and pretreatment weight. In addition, treatment week 12 serum E2 concentrations did not correlate with pretreatment weight, suggesting that the doses of LA used in these patients were adequate to suppress ovarian E2 production. Because estrone (E 1 ) and other steroids (i.e., androgens, progestins) were not measured in all patients, it remains uncertain 414
Friedman et al.
Communications-in-brief
80
60
..
40
% Deer•••• Uterine Volume
20
o -20
-40
4'0
50
eo
70
80 90 W.....tCkg)
100
110
120
130
140
Figure 1 Correlation between patient's weight and percent reduction in uterine volume after 12 weeks of LA treatment (r = -0.513, P < 0.001).
whether other estrogens or steroids may playa role in the growth of myomas and myometrium. Although untested, it may be hypothesized that heavier women have a greater ability to aromatize extraovarian androgens to estrogens (i.e., E 1 ) that may then affect myoma and uterine corpus size. Pretreatment uterine size is not predictive of the percent volume reduction. This finding differs from that of Coddington and colleagues (5) who suggested that larger uteri may be expected to have a greater relative size reduction than smaller uteri when treated with a GnRH-a. However, Coddington and co-workers studied only six patients, and a definitive relationship between uterine size changes and pretreatment size cannot be concluded from their small sample size. Clinically, when uterine size reduction is an important treatment goal, consideration should be given toward increasing the dose of a GnRH -a if incomplete E2 suppression (i.e., E2 > 30 pgjmL) is observed 4 weeks after treatment initiation. Similarly, heavier patients should be counseled that dramatic uterine size reduction may not occur, although other benefits of GnRH-agonist therapy (i.e., menstrual suppression) may be achieved. SUMMARY
A retrospective analysis of 104 women with leiomyomata uteri treated with LA for at least 12 weeks demonstrated a negative correlation between the percent reduction in uterine volume and serum E2 concentration at treatment week 12. The patient's age, height, or pretreatment uterine volume were not correlated with the degree of uterine shrinkage. Fertility and Sterility
Key Words: Gonadotropin-releasing hormone agonists, leuprolide, myoma, uterine volume, estradiol, reduction, predictors.
REFERENCES 1. Friedman AJ, Barbieri RL, Benacerraf BR, Schiff I. Treat-
ment of leiomyomata with intranasal or subcutaneous leuprolide, a gonadotropin-releasing hormone agonist. Fertil Steril1987;48:560-4. 2. Friedman AJ, Barbieri RL, Doubilet PM, Fine C, Schiff I. A randomized, double-blind trial of a gonadotropin releasinghormone agonist (leuprolide) with or without medroxypro-
Vol. 58, No.2, August 1992
gesterone acetate in the treatment of leiomyomata uteri. Fertil Steril 1988;49:404-9. 3. 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. 4. 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 Steril1989;51: 251-6. 5. 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.
Friedman et al.
Communications-in-brief
415
Vol. 58, No.2, August 1992
Copyright © 1992 The American Fertility Society
Printed on acid-free paper in U.S.A.
Predictors of uterine volume reduction in women with myomas treated with a gonadotropin-releasing hormone agonist*
Andrew J. Friedman, M.D.t Margaret Daly, R.N. Mary Juneau-Norcross, R.N. Mitchell S. Rein, M.D. Department of Obstetrics and Gynecology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts
Gonadotropin-releasing hormone agonists (GnRH-a) are commonly used to induce uterine shrinkage and menstrual suppression for both temporary relief of myoma-related symptoms and as a preoperative treatment before myomectomy or hysterectomy. Although mean uterine volume reduction has reportedly ranged from 40% to 50%, significant variability in uterine volume changes has been reported (1-4). Uterine volume has been reported to decrease as much as 80% in some cases, whereas no reduction or an actual increase in uterine size has occurred in others. The ability to predict those women who would be expected to exhibit significant reductions in uterine volume would have great potential utility, especially in women receiving GnRH-a in preparation for uterine surgery. In this study, several variables were evaluated as predictors of uterine volume reduction in 104 women with myomas who received the GnRH-a, leuprolide acetate (LA), for at least 12 weeks. MATERIALS AND METHODS
One hundred four premenopausal women with leiomyomata uteri received LA for at least 12 weeks. The results of LA treatment in many of these women have been reported in previous studies (1-4). Received February 10, 1992; revised and accepted. April 6, 1992.
* Supported in part by grant 7-M01-RR 02635-01 from the General Clinical Research Center, Brigham and Women's Hospital, Boston, Massachusetts. t Reprint requests: Andrew J. Friedman, M.D., Department of Obstetrics and Gynecology, Brigham and Women's Hospital, 75 Francis Street ASBI-2-104, Boston, Massachusetts 02115. Vol. 58, No.2, August 1992
Twenty-three women received LA, 0.5 mg/d subcutaneously, and 81 women received LA depot 3.75 mg intramuscularly every 28 days beginning anytime between the midluteal (i.e., cycle day 21) and early follicular phases (i.e., cycle day 3). In each woman, the uterus was measured in three dimensions (i.e., anteroposterior, length, width) with an Acuson 128 phased array variable focus system (Acuson, Inc., Mountview, CA) with a 3.5-MHz transducer before treatment and after receiving LA for 12 weeks. Uterine volume was calculated as an ellipsoid by the formula (0.524)(D 1)(D2)(D a) where Db D2, and Da were the diameters of the three measured uterine dimensions. Serum estradiol (E 2) was assayed using a direct 125I_E2 radioimmunoassay kit (Pantex, Santa Monica, CA) with a sensitivity of 4 pg/mL and intra-assay and interassay variations of 2.1 % and 4.6%, respectively. Data collected for each woman included age, height, weight, pretreatment uterine volume, pretreatment E2 concentrations in the midluteal phase, uterine volume at 12 weeks of treatment, and week 12 serum E2 concentrations. An unpaired t-test was used to test whether there was a significant difference in the decrease in mean uterine volume at 12 weeks between women with week 12 serum E2 concentrations ;5; 30 pg/mL and women with E2 levels > 30 pg/mL. Relationships between percent decrement in uterine volume at week 12 and other variables were tested for dependence using standard Pearson's product-moment correlations. RESULTS
The mean age of women in this study was 41.4
± 0.7 years (mean ± SE; range, 28 to 53 years), with Friedman et al.
Communications-in-brief
413
a mean height of 163.2 ± 0.7 cm (range 149 to 1,833 cm) and a mean weight of 68.9 ± 2.0 kg (range 41 to 166 kg). Mean pretreatment uterine volume was 727 ± 53 cm3 (range 96 to 2,810 cm3 ) and the mean week 12 uterine volume was 464 ± 40 cm3 (range 73 to 1,751 cm3 ). The mean decrease in uterine volume was 36.2% ± 2.0%, with a maximum decrease in uterine volume of 73.6% and a maximum increase in uterine volume of 24.3 %. Patients were also analyzed for degree of uterine size change. Four of 104 women (3.8%) had increases in uterine volume from 0.1 % to 25% by treatment week 12, 25 women (24.0%) had decreases in uterine volume from 0.1 % to 25%, 53 women (51.0%) had decreases in uterine volume from 25.1% to 50%, and 22 women (21.2%) had decreases in uterine volume> 50%. The mean pretreatment E2 concentration obtained in the midluteal phase was 122 ± 11.7 pgjml (range 68 to 227 pgjmL). At week 12, the mean E2 concentration was 24.3 ± 2.8 pgjmL (range 4 to 168 pgjmL). No significant correlation was noted between change in uterine volume at week 12 and the following variables: age, height, and pretreatment uterine volume. A significant negative correlation was noted between percent decrease in uterine volume at 12 weeks of treatment and week 12 serum E2 concentrations (r = -0.237, P = 0.03). The mean decrease in uterine volume for all women with week 12 serum E2 concentrations:::; 30 pgjmL was 43.1% ± 3.3% (range 12.0% to 73.6% decrease); in contrast, the mean decrease in uterine volume for all women with week 12 serum E2 concentrations> 30 pgjmL was 18.2% ± 5.3% (range 24.3% increase to 47.1 % decrease) (P < 0.01). Weight was also negatively correlated with the percent decrease in uterine volume (r = -0.513, P < 0.001, Fig. 1); however, weight was not correlated with serum E2 concentrations at 12 weeks of LA therapy (r = 0.014, P = 0.90). DISCUSSION
In this retrospective analysis of 104 women with myomas undergoing treatment with LA for at least 12 weeks, the percent decrease in uterine volume was found to correlate negatively with both serum E2 concentration at treatment week 12 and pretreatment weight. In addition, treatment week 12 serum E2 concentrations did not correlate with pretreatment weight, suggesting that the doses of LA used in these patients were adequate to suppress ovarian E2 production. Because estrone (E 1 ) and other steroids (i.e., androgens, progestins) were not measured in all patients, it remains uncertain 414
Friedman et al.
Communications-in-brief
80
60
..
40
% Deer•••• Uterine Volume
20
o -20
-40
4'0
50
eo
70
80 90 W.....tCkg)
100
110
120
130
140
Figure 1 Correlation between patient's weight and percent reduction in uterine volume after 12 weeks of LA treatment (r = -0.513, P < 0.001).
whether other estrogens or steroids may playa role in the growth of myomas and myometrium. Although untested, it may be hypothesized that heavier women have a greater ability to aromatize extraovarian androgens to estrogens (i.e., E 1 ) that may then affect myoma and uterine corpus size. Pretreatment uterine size is not predictive of the percent volume reduction. This finding differs from that of Coddington and colleagues (5) who suggested that larger uteri may be expected to have a greater relative size reduction than smaller uteri when treated with a GnRH-a. However, Coddington and co-workers studied only six patients, and a definitive relationship between uterine size changes and pretreatment size cannot be concluded from their small sample size. Clinically, when uterine size reduction is an important treatment goal, consideration should be given toward increasing the dose of a GnRH -a if incomplete E2 suppression (i.e., E2 > 30 pgjmL) is observed 4 weeks after treatment initiation. Similarly, heavier patients should be counseled that dramatic uterine size reduction may not occur, although other benefits of GnRH-agonist therapy (i.e., menstrual suppression) may be achieved. SUMMARY
A retrospective analysis of 104 women with leiomyomata uteri treated with LA for at least 12 weeks demonstrated a negative correlation between the percent reduction in uterine volume and serum E2 concentration at treatment week 12. The patient's age, height, or pretreatment uterine volume were not correlated with the degree of uterine shrinkage. Fertility and Sterility
Key Words: Gonadotropin-releasing hormone agonists, leuprolide, myoma, uterine volume, estradiol, reduction, predictors.
REFERENCES 1. Friedman AJ, Barbieri RL, Benacerraf BR, Schiff I. Treat-
ment of leiomyomata with intranasal or subcutaneous leuprolide, a gonadotropin-releasing hormone agonist. Fertil Steril1987;48:560-4. 2. Friedman AJ, Barbieri RL, Doubilet PM, Fine C, Schiff I. A randomized, double-blind trial of a gonadotropin releasinghormone agonist (leuprolide) with or without medroxypro-
Vol. 58, No.2, August 1992
gesterone acetate in the treatment of leiomyomata uteri. Fertil Steril 1988;49:404-9. 3. 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. 4. 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 Steril1989;51: 251-6. 5. 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.
Friedman et al.
Communications-in-brief
415