r
FERTILITY AND STERILITY
Vol. 54, No.6, December 1990
Copyright" 1990 The American Fertility Society
Printed on ocid-free paper in U.S.A.
Clinical predictors for buserelin acetate treatment of uterine fibroids: a prospective study of 40 women
Beverley J. Vollenhoven, M.D.*t:l: Paul Shekleton, M.D.* Jillian McDonald, S.R.N.* DavidL. Healy, Ph.D.*t Monash University and Medical Centre, Clayton, and Medical Research Centre, Prince Henry's Hospital, Melbourne, Victoria, Australia
Buserelin acetate, a luteinizing hormone-releasing hormone agonist, is known to be effective in the shrinkage of uterine fibroids. A prospective trial was undertaken (1) to compare the efficacy of intranasal (IN) and subcutaneous (SC) administration of buserelin acetate and (2) to assess if tumor regression correlated with fibroid size and/or patient age. Forty patients were randomly allocated to receive 6 months of either IN buserelin acetate (n = 21) or SC buserelin acetate (n = 19). Four patients did not complete the study and were excluded from statistical analysis. Fibroid regression occurred in all36 patients. Overall regression to 66% or less ofthe initial fibroid volume occurred in 70% of subjects. There was no significant difference in fibroid shrinkage between the two administration routes. A significant positive correlation was found between initial fibroid size and subsequent fibroid regression, with larger tumors being more likely to shrink than smaller fibroids. No correlation was found between the patient's age and the extent of fibroid regression. Fertil Steril54:1032, 1990
Uterine fibroids or leiomyomata are the most common tumors in humans, occurring in 20% to 25% of women over 30 years of age. 1 For such a common condition, surprisingly little is known about its etiology. Estrogen (E) and progesterone (P) are both thought to play a role in the formation of these tumors because increased numbers of both receptors have been found in fibroids compared with normal adjacent myometrium. 2-4 Epidermal growth factor (EGF) binding has also been found in fibroids, 5 as well as the recent finding that women treated with luteinizing hormone-releasing hormone (LH-RH) agonists have reduced EGF binding compared with untreated women. 6 Received April10, 1990; revised and accepted August 6, 1990. *Department of Obstetrics and Gynecology, Monash University and Medical Centre. t Medical Research Centre, Prince Henry's Hospital. :1: Reprint requests: Beverley J. Vollenhoven, M.D., Department of Obstetrics and Gynaecology, Monash Medical Centre, Clayton Campus, Clayton Road, Clayton 3168, Victoria, Australia.
1032
Vollenhoven et al.
Buserelin acetate and fibroids
It is now well known that LH-RH agonists, derived from peptide substitutions of native LH-RH, when given on a continuous basis cause pituitary down regulation ofLH-RH receptors and therefore decreased gonadotropin and sex steroid levels. The rationale behind the usage of LH-RH agonists for the treatment of uterine fibroids has been that the hypoestrogenism caused would decrease fibroid growth if the tumors are estrogen dependent for growth. One mechanism by which this decrease occurs may be because of a reduction in uterine arterial blood flow with a parallel increase in the resistance index, as reported by Shaw. 7 He demonstrated, by the use of ultrasound (US), an increase in the uterine arterial resistance index from 0.52 to 0.92 as uterine volume decreased from 656 to 386 mL. It has been shown, by histologic examination of fibroids obtained at hysterectomy from women treated with LH-RH agonists, that intense hyalinization is observed around blood vessels, further suggesting that decreased blood supply to the tumor may play a role in its shrinkage.8 Fertility and Sterility
Most studies have used nasal sprays or subcutaneous (SC) methods of delivery of the LH-RH agonists.9-12 Recently, implants and depot LH-RH agonist preparations given monthly or 3-month intervals have also been used. 13·14 Nasal sprays have undergone testing over 10 years and their efficacy is thought to be lower compared with other forms of administration. 15 This has also been suggested by Friedman and associates9who compared a group of patients receiving SC leuprolide acetate (LA) with those receiving intranasal (IN) LA. No significant fibroid regression occurred in the IN group and castrate levels of estradiol (E 2) were not reached. However, Maheux and others 10 successfully used IN buserelin acetate to induce fibroid shrinkage in their subjects, despite the lowest levels of serum E not being reached. Perl and associates16 reported three types ofE suppression curves: type 1 with rapidly suppressed levels; type 2 with erratic levels; and type 3 with incompletely suppressed levels. The greatest volume reduction was shown to occur with type 1 and 2 responses. A number of groups have used LH-RH agonists successfully to induce fibroid regression.9-14 Typically, there has been regression of fibroids to 50% of their initial volume. In most cases, complete shrinkage only occurred with the smaller tumors. The greatest fibroid regression occurs usually within the 1st 12 weeks of therapy. Although these treatments potentially have great benefits for women's health by avoiding major surgery, it is unclear as to which patients might benefit from this treatment. The aims of this study were (1) to compare the efficacy of both IN and SC buserelin acetate in shrinking uterine fibroids and (2) to assess the clinical predictors of patient age and fibroid size with tumor regression. This series is the largest group of patients so far reported. MATERIALS AND METHODS Patients
Forty women, aged 19 to 53 years (mean 36.6 years) with uterine fibroids were referred by other gynecologists for treatment. All fibroids could be measured morphometrically by abdominal or vaginal ultrasonography. Patients were accepted into the trial if they were nonsmokers, were willing to undertake at least 3 hours of weight-bearing exercise a week, and had an intake of 1,500 mg of calcium per day. All 40 patients were symptomatic: 26 suffered Vol. 54, No.6, December 1990
from menorrhagia, 17 were infertile for 3 or more years, 15 had pressure symptoms, 6 were anaemic, 4 had pelvic pain, 3 felt bloated and 1 woman had concurrent endometriosis. Some women suffered more than one symptom. The diagnosis of fibroids was made at operation in 23 (57.5%) women and clinically in 17 (42.5%) women. Three patients did not complete the study and are excluded from statistical analysis. Two of these women had pelvic pain on therapy, and 1 woman using IN buserelin acetate suffered rhinorrhea necessitating cessation of treatment. A patient in the SC group was noncompliant and likewise excluded. The study was approved by the Research and Ethics committee of the Monash Medical Centre. Informed consent was obtained from all patients before the commencement of therapy. Buserelin Acetate Delivery System
Buserelin acetate ([D- ser(But) 6,pro9Net]l9LHRH; Hoechst Pharmaceuticals, Melbourne, Australia) was administered either intranasally 12 X 100 JLg/d (1 insufflation per nostril6 times a day spread out as evenly as possible during the day) or as a SC pulse every 45 minutes (total dose 200 JLg/d) in a semicontinuous fashion throughout a 24hour period. Both methods of administration were commenced in the luteal phase of the menstrual cycle. Random allocation to either IN or SC administration was made. Twenty-one women received IN and 19 received SC buserelin acetate. Of the four patients who did not complete the study, two were in the SC group and two were in the IN group. Treatment Protocol
A weekly blood sample was taken for measurement of serum E 2, P, LH, and follicle-stimulating hormone (FSH) as part of monitoring response to therapy. The patients were reviewed frequently and underwent both clinical and gynecological examination. Ultrasound examinations using a RealTime Sector scanner (Sono Layer-V, model SSA90A; Toshiba Corporation, Tochigi-Ken, Japan) were performed by a single investigator (P.S.) for fibroid tumor morphometry at 6-week intervals in most cases. Fibroid volume was calculated by the formula 4/31rr1 X r 2 X r 3 where r 1 , r 2, r 3 were the three dimensions of the fibroid. When more than one fibroid was present in the same patient, the individual volumes were summed to give a total volume. Seventeen women had one fibroid, 16 had two, 4 had three, and 3 had more than three fibroids present. There was no significant difference beVollenhoven et al.
Buserelin acetate and fibroids
1033
r~l
:
,
,'
RESULTS Fibroid Response During Buserelin Acetate Therapy
40 ························································································································
20 ························································································································
.oW-~~~~~~~~~~~~~~~~_u
o
2
4
1
a
u
"
~
u
u
~
a
u
WilD
Figure 1 Mean percentage change in fibroid volume during buserelin acetate therapy (mean± SEM).
tween the numbers of fibroids in each treatment group. The IN group had 1.80 ± 0.16 fibroids and the SC group had 1.84 ± 0.23 fibroids (P > 0.05). Side effects of and compliance with drug therapy were recorded at each visit. Hormonal Assays Serum levels of E 2 and P were measured using the Coat-a-Count radioimmunoassay (RIA) kit (Diagnostic Products Corporation, Los Angeles, CA). Luteinizing hormone and FSH were measured by World Health Organization method manual RIA. Sensitivity limits for these assays were 20 pg/mL, 0.1 ng/mL, 0.24 IU/L, and 0.19 IU/L, respectively. Intra-assay and interassay coefficients of variation were 10% and 14.8%, and 5% and 9.1% for E 2 and P, and 5.2% and 4.4%, and 5.8% and 4.9% for FSH and LH.
All patients had a decrease in fibroid size during buserelin acetate treatment. Twenty-six of 36 patients (70%) had a decrease in fibroid volume to
FERTILITY AND STERILITY
Vol. 54, No.6, December 1990
Copyright" 1990 The American Fertility Society
Printed on ocid-free paper in U.S.A.
Clinical predictors for buserelin acetate treatment of uterine fibroids: a prospective study of 40 women
Beverley J. Vollenhoven, M.D.*t:l: Paul Shekleton, M.D.* Jillian McDonald, S.R.N.* DavidL. Healy, Ph.D.*t Monash University and Medical Centre, Clayton, and Medical Research Centre, Prince Henry's Hospital, Melbourne, Victoria, Australia
Buserelin acetate, a luteinizing hormone-releasing hormone agonist, is known to be effective in the shrinkage of uterine fibroids. A prospective trial was undertaken (1) to compare the efficacy of intranasal (IN) and subcutaneous (SC) administration of buserelin acetate and (2) to assess if tumor regression correlated with fibroid size and/or patient age. Forty patients were randomly allocated to receive 6 months of either IN buserelin acetate (n = 21) or SC buserelin acetate (n = 19). Four patients did not complete the study and were excluded from statistical analysis. Fibroid regression occurred in all36 patients. Overall regression to 66% or less ofthe initial fibroid volume occurred in 70% of subjects. There was no significant difference in fibroid shrinkage between the two administration routes. A significant positive correlation was found between initial fibroid size and subsequent fibroid regression, with larger tumors being more likely to shrink than smaller fibroids. No correlation was found between the patient's age and the extent of fibroid regression. Fertil Steril54:1032, 1990
Uterine fibroids or leiomyomata are the most common tumors in humans, occurring in 20% to 25% of women over 30 years of age. 1 For such a common condition, surprisingly little is known about its etiology. Estrogen (E) and progesterone (P) are both thought to play a role in the formation of these tumors because increased numbers of both receptors have been found in fibroids compared with normal adjacent myometrium. 2-4 Epidermal growth factor (EGF) binding has also been found in fibroids, 5 as well as the recent finding that women treated with luteinizing hormone-releasing hormone (LH-RH) agonists have reduced EGF binding compared with untreated women. 6 Received April10, 1990; revised and accepted August 6, 1990. *Department of Obstetrics and Gynecology, Monash University and Medical Centre. t Medical Research Centre, Prince Henry's Hospital. :1: Reprint requests: Beverley J. Vollenhoven, M.D., Department of Obstetrics and Gynaecology, Monash Medical Centre, Clayton Campus, Clayton Road, Clayton 3168, Victoria, Australia.
1032
Vollenhoven et al.
Buserelin acetate and fibroids
It is now well known that LH-RH agonists, derived from peptide substitutions of native LH-RH, when given on a continuous basis cause pituitary down regulation ofLH-RH receptors and therefore decreased gonadotropin and sex steroid levels. The rationale behind the usage of LH-RH agonists for the treatment of uterine fibroids has been that the hypoestrogenism caused would decrease fibroid growth if the tumors are estrogen dependent for growth. One mechanism by which this decrease occurs may be because of a reduction in uterine arterial blood flow with a parallel increase in the resistance index, as reported by Shaw. 7 He demonstrated, by the use of ultrasound (US), an increase in the uterine arterial resistance index from 0.52 to 0.92 as uterine volume decreased from 656 to 386 mL. It has been shown, by histologic examination of fibroids obtained at hysterectomy from women treated with LH-RH agonists, that intense hyalinization is observed around blood vessels, further suggesting that decreased blood supply to the tumor may play a role in its shrinkage.8 Fertility and Sterility
Most studies have used nasal sprays or subcutaneous (SC) methods of delivery of the LH-RH agonists.9-12 Recently, implants and depot LH-RH agonist preparations given monthly or 3-month intervals have also been used. 13·14 Nasal sprays have undergone testing over 10 years and their efficacy is thought to be lower compared with other forms of administration. 15 This has also been suggested by Friedman and associates9who compared a group of patients receiving SC leuprolide acetate (LA) with those receiving intranasal (IN) LA. No significant fibroid regression occurred in the IN group and castrate levels of estradiol (E 2) were not reached. However, Maheux and others 10 successfully used IN buserelin acetate to induce fibroid shrinkage in their subjects, despite the lowest levels of serum E not being reached. Perl and associates16 reported three types ofE suppression curves: type 1 with rapidly suppressed levels; type 2 with erratic levels; and type 3 with incompletely suppressed levels. The greatest volume reduction was shown to occur with type 1 and 2 responses. A number of groups have used LH-RH agonists successfully to induce fibroid regression.9-14 Typically, there has been regression of fibroids to 50% of their initial volume. In most cases, complete shrinkage only occurred with the smaller tumors. The greatest fibroid regression occurs usually within the 1st 12 weeks of therapy. Although these treatments potentially have great benefits for women's health by avoiding major surgery, it is unclear as to which patients might benefit from this treatment. The aims of this study were (1) to compare the efficacy of both IN and SC buserelin acetate in shrinking uterine fibroids and (2) to assess the clinical predictors of patient age and fibroid size with tumor regression. This series is the largest group of patients so far reported. MATERIALS AND METHODS Patients
Forty women, aged 19 to 53 years (mean 36.6 years) with uterine fibroids were referred by other gynecologists for treatment. All fibroids could be measured morphometrically by abdominal or vaginal ultrasonography. Patients were accepted into the trial if they were nonsmokers, were willing to undertake at least 3 hours of weight-bearing exercise a week, and had an intake of 1,500 mg of calcium per day. All 40 patients were symptomatic: 26 suffered Vol. 54, No.6, December 1990
from menorrhagia, 17 were infertile for 3 or more years, 15 had pressure symptoms, 6 were anaemic, 4 had pelvic pain, 3 felt bloated and 1 woman had concurrent endometriosis. Some women suffered more than one symptom. The diagnosis of fibroids was made at operation in 23 (57.5%) women and clinically in 17 (42.5%) women. Three patients did not complete the study and are excluded from statistical analysis. Two of these women had pelvic pain on therapy, and 1 woman using IN buserelin acetate suffered rhinorrhea necessitating cessation of treatment. A patient in the SC group was noncompliant and likewise excluded. The study was approved by the Research and Ethics committee of the Monash Medical Centre. Informed consent was obtained from all patients before the commencement of therapy. Buserelin Acetate Delivery System
Buserelin acetate ([D- ser(But) 6,pro9Net]l9LHRH; Hoechst Pharmaceuticals, Melbourne, Australia) was administered either intranasally 12 X 100 JLg/d (1 insufflation per nostril6 times a day spread out as evenly as possible during the day) or as a SC pulse every 45 minutes (total dose 200 JLg/d) in a semicontinuous fashion throughout a 24hour period. Both methods of administration were commenced in the luteal phase of the menstrual cycle. Random allocation to either IN or SC administration was made. Twenty-one women received IN and 19 received SC buserelin acetate. Of the four patients who did not complete the study, two were in the SC group and two were in the IN group. Treatment Protocol
A weekly blood sample was taken for measurement of serum E 2, P, LH, and follicle-stimulating hormone (FSH) as part of monitoring response to therapy. The patients were reviewed frequently and underwent both clinical and gynecological examination. Ultrasound examinations using a RealTime Sector scanner (Sono Layer-V, model SSA90A; Toshiba Corporation, Tochigi-Ken, Japan) were performed by a single investigator (P.S.) for fibroid tumor morphometry at 6-week intervals in most cases. Fibroid volume was calculated by the formula 4/31rr1 X r 2 X r 3 where r 1 , r 2, r 3 were the three dimensions of the fibroid. When more than one fibroid was present in the same patient, the individual volumes were summed to give a total volume. Seventeen women had one fibroid, 16 had two, 4 had three, and 3 had more than three fibroids present. There was no significant difference beVollenhoven et al.
Buserelin acetate and fibroids
1033
r~l
:
,
,'
RESULTS Fibroid Response During Buserelin Acetate Therapy
40 ························································································································
20 ························································································································
.oW-~~~~~~~~~~~~~~~~_u
o
2
4
1
a
u
"
~
u
u
~
a
u
WilD
Figure 1 Mean percentage change in fibroid volume during buserelin acetate therapy (mean± SEM).
tween the numbers of fibroids in each treatment group. The IN group had 1.80 ± 0.16 fibroids and the SC group had 1.84 ± 0.23 fibroids (P > 0.05). Side effects of and compliance with drug therapy were recorded at each visit. Hormonal Assays Serum levels of E 2 and P were measured using the Coat-a-Count radioimmunoassay (RIA) kit (Diagnostic Products Corporation, Los Angeles, CA). Luteinizing hormone and FSH were measured by World Health Organization method manual RIA. Sensitivity limits for these assays were 20 pg/mL, 0.1 ng/mL, 0.24 IU/L, and 0.19 IU/L, respectively. Intra-assay and interassay coefficients of variation were 10% and 14.8%, and 5% and 9.1% for E 2 and P, and 5.2% and 4.4%, and 5.8% and 4.9% for FSH and LH.
All patients had a decrease in fibroid size during buserelin acetate treatment. Twenty-six of 36 patients (70%) had a decrease in fibroid volume to
