Treatment of uterine fibroids: Current findings with gonadotropin -releasing hormone agonists G. David Adamson, MD Palo Alto, California The gonadotropin-releasing hormone agonists have potential benefit as presurgical adjuncts in the management of uterine leiomyomas or fibroids. Uterine fibroids contain estrogen receptors and are responsive to therapeutic hormonal manipulation; gonadotropin-releasing hormone agonists are effective by inducing a state of hypoestrogenism. Clinical trials with gonadotropin-releasing hormone agonists consistently have demonstrated efficacy for decreasing both myoma size and uterine volume. The advantages of the preoperative use of gonadotropin-releasing hormone agonists include a reduction in uterine and myoma size and vascularity and potentially improved operative technique and uterine cavity integrity. Ongoing clinical trials will be needed to confirm the role of gonadotropin-releasing hormone agonists in the treatment of uterine fibroids. (AM J OBSTET GVNECOL 1992;166:746-51.)
Key words: Gonadotropin-releasing hormone analog, leiomyoma, uterine fibroids, leuprolide, nafarelin Uterine fibroids is a common medical problem among women, and surgery is often recommended for management. Recently, gonadotropin-releasing hormone (GnRH) agonists have been investigated for use in uterine fibroid disease, but many questions remain about their role in overall management. To help clarify the role of GnRH agonists in myomatous uteri, this article will review the effect of GnRH agonists on uterine myomas and the uterus. The clinical implications of these actions and the potential disadvantages of GnRH agonists will also be discussed. Finally, a brief summary of the current role of GnRH agonists in the management of uterine myomas will be offered.
Uterine fibroids Leiomyomas or uterine fibroids are neoplasms of the smooth muscle found in about 20% of women over the age of 30 years. I Although uterine leiomyomas are the most common solid tumor of the female genital tract, they are benign. Thus therapeutic intervention is not required for all women with uterine fibroids. Indications for the treatment of uterine myomas include menorrhagia with iron deficiency anemia, uterine pressure or pain, rapidly increasing fibroid size, recurrent abortion with endometrial cavity distortion, and infertility with endometrial cavity distortion. Unexplained or refractory infertility may also be an indication for myomectomy.2 Until recently, there has been no generally accepted medical therapy for the management of leiomyomas. From the Fertility Physicians of Northern California. Reprints are not available. 6/0/34757
746
Rather, management of patients with symptoms of uterine myomas has traditionally been surgical ranging from myomectomy to hysterectomy. Of the 650,000 hysterectomies performed annually in the United States, approximately 27% or 175,000 are performed for uterine myomas. s Myomectomy is performed in about 18,000 patients per year. Myomectomy has a recurrence rate of 15% (range, 4% to 59%) and a repeat operation rate of 10% (range, 3% to 21 %), and subsequent hysterectomy is required in an additional 1% to 5% of patients'" 5 Although the pathogenesis of myomas is not well established, it has been recognized that fibroid growth and maintenance are stimulated by estrogen and are affected by hormonal cyclic changes. 6 Estrogen and progesterone receptors have been identified in myomatous tissue.' Because leiomyomas can be influenced by changes at the estrogen and progesterone receptors, GnRH agonists have been investigated as a potential treatment. Several pilot and small studies have been reported in which GnRH agonists were evaluated for the treatment of uterine fibroids. l • 2. 8-11 Potential benefits of GnRH agonist therapy are a reduction in uterine fibroid size and uterine volume, decreased preoperative and perioperative blood loss, and an improvement in operative conditions.
Effect of GnRH agonists on fibroid size A primary effect of GnRH agonists on uterine fibroids should be to decrease fibroid size. In one study, the effect of daily administration of nafarelin on uterine and myoma size was evaluated in 10 patients with the use of magnetic resonance imaging. 12 After 6
Treatment of uterine fibroids with GnRH agonists
Volume 166 Number 2
50
747
0 Buserelin
fJ Goserelin
40 % of
Women Having Change In Fibroid Volume
30 20 10 0
60
Percent Reduction in Fibroid Volume
Fig. 1. Proportion of women having a change in fibroid volume from baseline to 6 months after treatment with buserelin (n = 21) or goserelin (n = 21). (Modified from Costantini et al. Eur J Obstet Gynecol Reprod Bioi 1990;37:63-9, by permission of Elsevier Science Publishers.) months of treatment, the size of the largest myoma decreased by a mean of 46% from baseline in 9 of 10 women. Uterine volume decreased by an average of 57% in all treated patients. Of note, both small and large myomas responded to nafarelin therapy, but consistent with other trials, myomas became enlarged again after discontinuation of nafarelin in several women. In a more recent trial, Costantini et al. 13 compared the effects of 6 months of treatment with intranasal buserelin or subcutaneous goserelin on myoma size. A reduction of more than 30% in myoma volume was seen in 34 of 42 (81 %) patients, and no difference was seen between the two GnRH agonists (Fig. 1). As reported in other clinical trials, regrowth of the myomas followed the discontinuation of therapy.14 One of the largest trials conducted to date with a GnRH agonist was a multicenter, randomized, placebocontrolled trial in which the effects of intranasal nafarelin on menstrual blood loss and uterine and fibroid volume were evaluated in 166 patients scheduled for elective hysterectomy (Ylikorkala, personal communication). Patients scheduled for hysterectomy for nonmalignant conditions, including uterine fibroids, menorrhagia, or pelvic pain, were evaluated by ultrasound examination. Patients were randomized in a 2: 1 ratio to treatment with either intranasal nafarelin, 200 ILg twice daily, or placebo for 3 months or until hysterectomy. In patients with fibroids, the total volume of the three largest fibroids decreased by 31 % from admission to 3 months in the nafarelin group but increased by 1.2% in the placebo group (p = 0.024; Fig. 2). Assessment of the largest fibroid at the time of surgery showed a decrease in the volume of the largest fibroid with nafarelin compared with placebo (p = 0.055). All the studies done to date with GnRH agonists show a variable but significant decrease in myoma size; however, in most instances, myomas returned to pretreat-
ment size after discontinuation of GnRH agonist therapy. The reasons for this response within a few months to GnRH agonist therapy have been studied. Pasqualini et al. 15 looked at the effect of a GnRH agonist, decapepty!, on hormone levels and receptors in uterine myomas and found that myoma tissue was very sensitive to changes in hormone levels. This occurs because myoma tissue has receptors for estrogen and progesterone and thus is affected by both cyclic changes in hormone levels and pharmacologic therapy such as GnRH agonists, which alter hormonal levels. 16 The number of estrogen receptors decreases during the postovulatory phase and is greatest during the follicular phase. Further, estrogen and progesterone receptors are more numerous in submucous than subserosal myomas. This has led to the hypothesis that submucous myomas may respond better to GnRH agonist therapy than large subserosal myomas. In addition, the effect of GnRH agonists on myomas is to decrease cell size and intracellular matrix but without changes in the number of cells. Therefore it is not surprising that after the GnRH agonist is discontinued, myomas return to pretreatment size. Effect of GnRH agonists on uterine size
GnRH agonists are also known to decrease uterine size. In a prospective randomized trial, Friedman et al. 14 demonstrated a reduction in uterine volume with leuprolide acetate. Eighteen women were randomly assigned to receive monthly intramuscular injections of leuprolide or placebo for 24 weeks. A significant (p < 0.05) reduction in uterine volume was noted at 12 and at 24 weeks in the leuprolide group compared with pretreatment volume (Fig. 3). However, uterine volume returned to 88% of pretreatment levels by 3 months after discontinuation of GnRH therapy. In another large double-blind multicenter trial, leu-
February 1992 Am J Obstet Gynecol
748 Adamson
10
...... ~
.,
0
01
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.c
.,
0
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-20
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'0 -30
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1
Treatment Month No. of Patients
SO
45
77
44
74
43
Fig. 2. Median percentage change in volume of the largest three fibroids (Ylikorkala, personal communication). p = 0.024 for nafarelin vs placebo by two-way analysis of variance.
o
Leuprolide (n = 1S)
121 Placebo (n = 20)
Change in Uterine Volume (cm3)
Pretreatment
24 12 Treatment Week
Posttreatment (3 months)
Fig. 3. Change in uterine volume (mean ± standard error) during treatment with depot leuprolide acetate or placebo in women with uterine fibroids. 14 *p < 0.05 vs pretreatment by the Dunnett t test. (From Friedman AJ, Harrison-Atlas D, Barbieri RL, Benacerraf B, Gleas~:m R, Schiff I. A randomized, placebo-controlled, double-blind study evaluating the efficacy of leuprolide acetate depot in the treatment of uterine leiomyomata. Fertil Steril 1989;51:251-6. Reproduced with permission of the publisher, The American Fertility Society.)
prolide acetate or placebo were administered to 128 women with leiomyomata uteri every 4 weeks for 24 weeks. 17 Mean uterine volume decreased by 45% in patients treated with leuprolide compared with a 5% increase in those given placebo. Uterine volume returned to pretreatment size by 24 weeks after leu prolide was stopped. The Finnish study that used nafarelin also showed that both the length and volume of the myomatous uteri were decreased significantly (p < 0.05) in the nafarelin group compared with the placebo group (Ylikorkala, personal communication). These findings were confirmed during surgery where the uterine weight was measured. There was a significant decrease in uterine
weight in the nafarelin group compared with the placebo group in all patients and in the patients with fibroids only. Thus the results from these studies demonstrate that GnRH agonists reduce uterine and myoma size.
Implications of GnRH treatment of uterine fibroids
With a documented reduction in uterine and myoma size, the question becomes "What are the implications of the effects of GnRH agonists in the clinical management of myomas?" One of the potential benefits of preoperative GnRH agonist treatment of uterine fibroids is a reduction in menstrual blood loss. Results
Treatment of uterine fibroids with GnRH agonists 749
Volume 166 Number 2
60
o
Nafarelin (n = 91)
~
Placebo (n = 48)
o
IZI
Control Cn = 14) Goserelin (n
= 13)
50 400
l
40
c
30
11.
20
1/1
~
350 300
~
250
4D
E 200 ::I
"0 > 150
10 0
400
350
100 None
Mild
Moderate
Severe
Fig. 4. Severity of menstrual blood loss at 3 months in women treated with nafarelin or placebo before elective hysterectomy (Ylikorkala, personal communication). p < 0.001 for nafarelin vs placebo by Cochran-Mantel-Haenszel test.
from the Finnish study confirm this effect (Ylikorkala, personal communication). In patients with severe blood loss at baseline, 55% of those randomly assigned to nafarelin therapy had no bleeding at the end of the 3month treatment period compared with 10% of the placebo-treated patients (p < 0.001). In contrast, 48% of patients receiving placebo continued to have severe menstrual bleeding at the end of therapy compared with only 14% of patients receiving nafarelin (Fig. 4). In addition, a mean increase of 4.2% in hemoglobin levels was noted before surgery in patients treated with nafarelin compared with a decrease of 2.7% in the placebo group (p = 0.032). In another study, patients were treated with 3.6 mg of subcutaneous goserelin every 28 days for 6 months. 10 In addition to a reduction in myoma and uterine size, there was a reduction in both menstrual blood loss and blood loss at the time of surgery (Fig. 5). Similar findings were reported in the large leuprolide study.17 In addition to improvement in symptoms in most patients, 37 of 38 patients (97%) with menorrhagia at baseline had resolution by the end of treatment with leuprolide. The decrease in blood loss and the increase in hemoglobin and hematocrit afforded by GnRH agonist therapy have several potential benefits, although it must be emphasized that prospective randomized studies proving these potential benefits have not yet been performed. The patient's hematocrit level may be sufficient to allow the patient to give autologous blood donations before surgery. Further, the lessened perioperative blood loss may reduce the need for blood transfusion and hysterectomy at the time of surgery. Thus the risks associated with blood transfusion, which are often overlooked or underestimated, may be re-
50 0 Uterine Volume
Operative Blood Loss
Fig. 5. Uterine volume and operative blood loss in women with symptomatic uterine fibroids treated for 3 months before elective hysterectomy. p < 0.01 for goserelin vs placebo by Wilcoxon two-sample test. (Modified from Lumsden MA et al. Lancet 1987;1:36-7.)
Table I. Potential advantages of a reduction in uterine and myoma size by GnRH agonists Reduced vascularity • Reduced menorrhagia • Increased hematocrit and iron • Autologous donation • Less operative blood loss • Reduced risk of blood transfusion • Reduced risk of hepatitis Operative technique • Hysterectomy less likely • Operative laparoscopy more likely • Fewer, smaller incisions • Less tissue trauma • Less risk of injury • Pfannenstiel incision more feasible • Vaginal hysterectomy more feasible Integrity of uterine cavity • Hysteroscopic approach • Avoidance of uterine cavity at laparotomy
duced. Between 8% and 18% of patients require blood or blood products at surgery; the current risk of hepatitis is approximately 8% per transfusion. 5 • 18. 19 Other potential advantages from the use of GnRH agonists may result from a reduction of uterine myoma size. These include the use of more conservative surgery; that is, the condition may be managed with myomectomy rather than hysterectomy. Smaller and fewer incisions may result in decreased tissue trauma and increased preservation of normal tissue, possibly reducing adhesion formation after surgery. Other potential advantages are listed in Table I.
750
Adamson
Disadvantages of GnRH agonist therapy Treatment with GnRH agonists is not benign. The known hypoestrogenic side effects are hot flashes and bone loss. About 2% of patients receiving GnRH agonist therapy can experience a very profuse vaginal hemorrhage requiring immediate surgical management. 20 This serious clinical problem has been reported to date only in patients with submucous myomas. The cause of this adverse event is thought to be a reduction in myoma size and a loss of mechanical compression of the vessels within the uterus. Also, painful fibroid degeneration may occur. There is also concern about making the fibroid so small as to avoid detection at the time of surgery. Some investigators have been concerned that myomas may be reduced to an undetectable size by preoperative GnRH agonist use. Results from a recent trial of buserelin before myomectomy suggested that this phenomenon occurs.21 In this randomized trial, a 44% decrease in uterine volume was observed during buserelin therapy in eight patients compared with no change in 16 untreated control patients. Intraoperative blood loss and postoperative morbidity did not differ between groups. However, at the 6-month postoperative evaluation, only 2 of 16 (13%) patients in the untreated group had myomas smaller than 1.5 cm in size compared with 5 of 8 (63%) patients in the buserelin group. These data suggest that small myomas may have been missed at the time of surgery because of preoperative treatment with buserelin. The results of this study need to be confirmed by others, and if true, its clinical relevance established.
Strategies for managing uterine myomas Despite the promising results of studies with GnRH agonists for the treatment of uterine fibroids, surgery remains the treatment of choice. Several different procedures are appropriate including myomectomy by either laparoscopy, laparotomy, or hysteroscopy or hysterectomy by various surgical approaches. However, the use of a GnRH agonist as a preoperative adjunct has some potential benefits to the patient. Preoperative use of GnRH agonists may increase the feasibility of using myomectomy instead of hysterectomy, increase the use of laparoscopic, hysteroscopic, or vaginal procedures, preserve normal uterine tissue, facilitate the operative technique, and reduce blood loss. The choice of therapy will depend on the surgical aspects of treatment, but also on the size and number of myomata, the age of the patient, and the desire to preserve fertility and uterine function. One innovative strategy for managing uterine fibroids with medical therapy only is to combine the GnRH agonist with an estrogen-progestin combination. In a preliminary trial, five women with leiomyomata
February 1992
Am J Obstet Gynecol
uteri were treated with leuprolide for 24 weeks. 22 After 3 months, conjugated estrogens were added on days I to 25 and medroxyprogesterone acetate from days 16 to 25. Patients were followed for as long as 2 years. A 49% decrease in uterine volume was seen at 3 months, but no further decrease was seen during the next 2 years. There was also a decrease in vasomotor symptoms, and bone density was preserved. These results were encouraging, but additional data obtained on more patients and a longer duration of study have shown a regrowth of the myomas in some patients taking this regimen. This confirms not only that leiomyomata and myometrium are estrogen sensitive, but suggests that an estrogenic threshold exists for uterine growth. It can be seen that different treatment strategies that use GnRH agonists show promise, but the optimal approach to medical treatment of uterine fibroids is unclear. Further studies, many currently ongoing, will help us understand and use GnRH agonists better in the future. In conclusion, results from clinical trials have consistently shown the efficacy of GnRH agonists as a preoperative adjunct for reducing myoma and uterine size and preoperative and perioperative blood loss. Uterine myomas are very sensitive to hormonal changes probably mediated through estrogen and progesterone receptors, the likely mechanism by which GnRH agonists can effect changes. Although the role of the GnRH agonists in the management of uterine leiomyoma has not been fully defined, use as a presurgical adjunct may allow preservation of uterine tissue because of removal of smaller myomas and more conservative surgical procedures.
REFERENCES 1. Healy DL, Lawson SR, Abbott M, Baird DT, Fraser HM.
2.
3.
4. 5. 6.
7.
Toward removing uterine fibroids without surgery: subcutaneous infusion of a luteinizing hormone-releasing hormone agonist commencing in the luteal phase. ] Clin Endocrinol Metab 1986;63:619-25. Coddington CC, Collins RL, Shawker TH, Anderson R, Loriaux DL, Winkel CA. Long-acting gonadotropin hormone-releasing hormone analog used to treat uteri. Ferti! Steril 1986;45:624-9. National Center for Health Statistics. Hysterectomies in the United States 1965-84. U.S. Department of Health, Education, and Welfare. DHEW publication no. (PHS) 881753. (Vital and health statistics; series B; no 92). Malone LJ. Myomectomy: recurrence after removal of solitary and multiple myomas. Obstet Cynecol 1969;34: 200-3. Berkeley AS, DeCherney AH, Polan ML. Abdominal myomectomy and subsequent fertility. Surg Cynecol Obstet 1983; 156:319-24. Friedman A], Lobel SM, Rein MS, Barbieri RL. Efficacy and safety considerations in women with uterine leiomyomas treated with gonadotropin-releasing hormone agonists: the estrogen threshold hypothesis. AM] OBSTET CYNECOL 1990; 163: 1114-9. Tamaya T, Fujimoto J, Okada H. Comparison of cellular
Volume 166 Number 2
8.
9.
10. II.
12.
13.
14.
levels of steroid receptors in uterine leiomyoma and myometrium. Acta Gynecol Scand 1985;64:307-9. Filicori M, Hall DA, Loughlin JS, Rivier J, Vale W, Crowley WF Jr. 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. Maheux R, Guilloteau C, Lemay A, Bastide A, Fazekas ATA. Regression of leiomyomata uteri following hypoestrogenism induced by repetitive luteinizing hormone-releasing hormone agonist treatment: preliminary report. Fertil Steril 1984;42:644-6. Lumsden MA, West C, Baird DT. Goserelin therapy be fore surgery for uterine fibroids. Lancet 1987;1:36-7. Friedman AJ, Rein MS, Harrison-Atlas D, Garfield JM, Doubilet PM. A randomized, placebo-controlled, doubleblind study evaluating leuprolide acetate depot treatment before myomectomy. Ferti! Steril 1989;52:728-33. Andreyko JL, Blumenfeld Z, Marshall LA, Monroe SE, Hricak H,Jaffe RB. Use of an agonistic analog of gonadotropin-releasing hormone (nafarelin) to treat leiomyomas: assessment by magnetic resonance imaging. AM J OBSTET GYNECOL 1988;158:903-10. Costantini S, Anserini P, Valenzana M, Remorgida V, Venturini PL, De Cecco L. Luteinizing hormone-releasing hormone analog therapy of uterine fibroid: analysis of results obtained with buserelin administered intranasally and goserelin administered subcutaneously as a monthly depot. Eur J Obstet Gynecol Reprod BioI 1990;37:63-9. Friedman AJ, Benacerraf B, Harrison-Atlas D, Gleason R, Barbieri RL, Shiff 1. A randomized, placebo-controlled, double-blind study evaluating the efficacy of leuprolide acetate depot in the treatment of uterine leiomyomata. Ferti! Steril 1989;51:251-6.
Treatment of uterine fibroids with GnRH agonists
751
15. Pasqualini JR, Cornier E, Grenier J, Vella C, Schatz B, Netter A. Effect of decapeptyl, an agonistic analog of gonadotropin-releasing hormone on estrogens, estrogen sulfates, and progesterone receptors in leiomyoma and myometrium. Fertil Steril 1990;6: 10 12-1. 16. Marugo M, Centonze M, Bernasconi D, Fazzuoli L, Berta S, Giordana G. Estrogen and progesterone receptors in uterine leiomyomas. Acta Obstet Gynecol Scand 1989;68: 731-5. 17. Friedman AJ, Hoffman DI, Comite F, Browneller RW, Miller JD. Treatment of leiomyomata uteri with leu prolide acetate depot: a double-blind, placebo-controlled, multicenter study. The Leuprolide Study Group. Obstet Gynecol 1991 ;77:720-5. 18. Dicker RC, GreenspanJR, Strauss LT, et al. Complications of abdominal and vaginal hysterectomy among women of reproductive age in the United States. AM J OBSTET GyNECOL 1982;144:841-6. 19. Koziol DE, Holland PV, Alling DW, et al. Antibody to hepatitis B core antigen as a paradoxical marker for nonA, non-B hepatitis agents in donated blood. Ann Intern Med 1986; 104:488-95. 20. Friedman AJ. Vaginal hemorrhage associated with degenerating submucous leiomyomata during leuprolide acetate treatment. Ferti! Steril 1989;52: 152-4. 21. Fedele L, Vercellini P, Bianchi S, Brioschi D, Dorta M. Treatment with GnRH agonists before myomectomy and the risk of short-term myoma recurrence. Br J Obstet Gynaecol 1990;97:393-6. 22. Friedman AJ. Treatment of leiomyomata uteri with shortterm leuprolide followed by leuprolide plus estrogen-progestin hormone replacement therapy for 2 years: a pilot study. Fertil Steril 1989;51 :526-8.
Key words: Gonadotropin-releasing hormone analog, leiomyoma, uterine fibroids, leuprolide, nafarelin Uterine fibroids is a common medical problem among women, and surgery is often recommended for management. Recently, gonadotropin-releasing hormone (GnRH) agonists have been investigated for use in uterine fibroid disease, but many questions remain about their role in overall management. To help clarify the role of GnRH agonists in myomatous uteri, this article will review the effect of GnRH agonists on uterine myomas and the uterus. The clinical implications of these actions and the potential disadvantages of GnRH agonists will also be discussed. Finally, a brief summary of the current role of GnRH agonists in the management of uterine myomas will be offered.
Uterine fibroids Leiomyomas or uterine fibroids are neoplasms of the smooth muscle found in about 20% of women over the age of 30 years. I Although uterine leiomyomas are the most common solid tumor of the female genital tract, they are benign. Thus therapeutic intervention is not required for all women with uterine fibroids. Indications for the treatment of uterine myomas include menorrhagia with iron deficiency anemia, uterine pressure or pain, rapidly increasing fibroid size, recurrent abortion with endometrial cavity distortion, and infertility with endometrial cavity distortion. Unexplained or refractory infertility may also be an indication for myomectomy.2 Until recently, there has been no generally accepted medical therapy for the management of leiomyomas. From the Fertility Physicians of Northern California. Reprints are not available. 6/0/34757
746
Rather, management of patients with symptoms of uterine myomas has traditionally been surgical ranging from myomectomy to hysterectomy. Of the 650,000 hysterectomies performed annually in the United States, approximately 27% or 175,000 are performed for uterine myomas. s Myomectomy is performed in about 18,000 patients per year. Myomectomy has a recurrence rate of 15% (range, 4% to 59%) and a repeat operation rate of 10% (range, 3% to 21 %), and subsequent hysterectomy is required in an additional 1% to 5% of patients'" 5 Although the pathogenesis of myomas is not well established, it has been recognized that fibroid growth and maintenance are stimulated by estrogen and are affected by hormonal cyclic changes. 6 Estrogen and progesterone receptors have been identified in myomatous tissue.' Because leiomyomas can be influenced by changes at the estrogen and progesterone receptors, GnRH agonists have been investigated as a potential treatment. Several pilot and small studies have been reported in which GnRH agonists were evaluated for the treatment of uterine fibroids. l • 2. 8-11 Potential benefits of GnRH agonist therapy are a reduction in uterine fibroid size and uterine volume, decreased preoperative and perioperative blood loss, and an improvement in operative conditions.
Effect of GnRH agonists on fibroid size A primary effect of GnRH agonists on uterine fibroids should be to decrease fibroid size. In one study, the effect of daily administration of nafarelin on uterine and myoma size was evaluated in 10 patients with the use of magnetic resonance imaging. 12 After 6
Treatment of uterine fibroids with GnRH agonists
Volume 166 Number 2
50
747
0 Buserelin
fJ Goserelin
40 % of
Women Having Change In Fibroid Volume
30 20 10 0
60
Percent Reduction in Fibroid Volume
Fig. 1. Proportion of women having a change in fibroid volume from baseline to 6 months after treatment with buserelin (n = 21) or goserelin (n = 21). (Modified from Costantini et al. Eur J Obstet Gynecol Reprod Bioi 1990;37:63-9, by permission of Elsevier Science Publishers.) months of treatment, the size of the largest myoma decreased by a mean of 46% from baseline in 9 of 10 women. Uterine volume decreased by an average of 57% in all treated patients. Of note, both small and large myomas responded to nafarelin therapy, but consistent with other trials, myomas became enlarged again after discontinuation of nafarelin in several women. In a more recent trial, Costantini et al. 13 compared the effects of 6 months of treatment with intranasal buserelin or subcutaneous goserelin on myoma size. A reduction of more than 30% in myoma volume was seen in 34 of 42 (81 %) patients, and no difference was seen between the two GnRH agonists (Fig. 1). As reported in other clinical trials, regrowth of the myomas followed the discontinuation of therapy.14 One of the largest trials conducted to date with a GnRH agonist was a multicenter, randomized, placebocontrolled trial in which the effects of intranasal nafarelin on menstrual blood loss and uterine and fibroid volume were evaluated in 166 patients scheduled for elective hysterectomy (Ylikorkala, personal communication). Patients scheduled for hysterectomy for nonmalignant conditions, including uterine fibroids, menorrhagia, or pelvic pain, were evaluated by ultrasound examination. Patients were randomized in a 2: 1 ratio to treatment with either intranasal nafarelin, 200 ILg twice daily, or placebo for 3 months or until hysterectomy. In patients with fibroids, the total volume of the three largest fibroids decreased by 31 % from admission to 3 months in the nafarelin group but increased by 1.2% in the placebo group (p = 0.024; Fig. 2). Assessment of the largest fibroid at the time of surgery showed a decrease in the volume of the largest fibroid with nafarelin compared with placebo (p = 0.055). All the studies done to date with GnRH agonists show a variable but significant decrease in myoma size; however, in most instances, myomas returned to pretreat-
ment size after discontinuation of GnRH agonist therapy. The reasons for this response within a few months to GnRH agonist therapy have been studied. Pasqualini et al. 15 looked at the effect of a GnRH agonist, decapepty!, on hormone levels and receptors in uterine myomas and found that myoma tissue was very sensitive to changes in hormone levels. This occurs because myoma tissue has receptors for estrogen and progesterone and thus is affected by both cyclic changes in hormone levels and pharmacologic therapy such as GnRH agonists, which alter hormonal levels. 16 The number of estrogen receptors decreases during the postovulatory phase and is greatest during the follicular phase. Further, estrogen and progesterone receptors are more numerous in submucous than subserosal myomas. This has led to the hypothesis that submucous myomas may respond better to GnRH agonist therapy than large subserosal myomas. In addition, the effect of GnRH agonists on myomas is to decrease cell size and intracellular matrix but without changes in the number of cells. Therefore it is not surprising that after the GnRH agonist is discontinued, myomas return to pretreatment size. Effect of GnRH agonists on uterine size
GnRH agonists are also known to decrease uterine size. In a prospective randomized trial, Friedman et al. 14 demonstrated a reduction in uterine volume with leuprolide acetate. Eighteen women were randomly assigned to receive monthly intramuscular injections of leuprolide or placebo for 24 weeks. A significant (p < 0.05) reduction in uterine volume was noted at 12 and at 24 weeks in the leuprolide group compared with pretreatment volume (Fig. 3). However, uterine volume returned to 88% of pretreatment levels by 3 months after discontinuation of GnRH therapy. In another large double-blind multicenter trial, leu-
February 1992 Am J Obstet Gynecol
748 Adamson
10
...... ~
.,
0
01
c -10 as
.c
.,
0
E
-20
0 Nafarelin rJ Placebo
:::J
'0 -30
>
-40
3
'2
1
Treatment Month No. of Patients
SO
45
77
44
74
43
Fig. 2. Median percentage change in volume of the largest three fibroids (Ylikorkala, personal communication). p = 0.024 for nafarelin vs placebo by two-way analysis of variance.
o
Leuprolide (n = 1S)
121 Placebo (n = 20)
Change in Uterine Volume (cm3)
Pretreatment
24 12 Treatment Week
Posttreatment (3 months)
Fig. 3. Change in uterine volume (mean ± standard error) during treatment with depot leuprolide acetate or placebo in women with uterine fibroids. 14 *p < 0.05 vs pretreatment by the Dunnett t test. (From Friedman AJ, Harrison-Atlas D, Barbieri RL, Benacerraf B, Gleas~:m R, Schiff I. A randomized, placebo-controlled, double-blind study evaluating the efficacy of leuprolide acetate depot in the treatment of uterine leiomyomata. Fertil Steril 1989;51:251-6. Reproduced with permission of the publisher, The American Fertility Society.)
prolide acetate or placebo were administered to 128 women with leiomyomata uteri every 4 weeks for 24 weeks. 17 Mean uterine volume decreased by 45% in patients treated with leuprolide compared with a 5% increase in those given placebo. Uterine volume returned to pretreatment size by 24 weeks after leu prolide was stopped. The Finnish study that used nafarelin also showed that both the length and volume of the myomatous uteri were decreased significantly (p < 0.05) in the nafarelin group compared with the placebo group (Ylikorkala, personal communication). These findings were confirmed during surgery where the uterine weight was measured. There was a significant decrease in uterine
weight in the nafarelin group compared with the placebo group in all patients and in the patients with fibroids only. Thus the results from these studies demonstrate that GnRH agonists reduce uterine and myoma size.
Implications of GnRH treatment of uterine fibroids
With a documented reduction in uterine and myoma size, the question becomes "What are the implications of the effects of GnRH agonists in the clinical management of myomas?" One of the potential benefits of preoperative GnRH agonist treatment of uterine fibroids is a reduction in menstrual blood loss. Results
Treatment of uterine fibroids with GnRH agonists 749
Volume 166 Number 2
60
o
Nafarelin (n = 91)
~
Placebo (n = 48)
o
IZI
Control Cn = 14) Goserelin (n
= 13)
50 400
l
40
c
30
11.
20
1/1
~
350 300
~
250
4D
E 200 ::I
"0 > 150
10 0
400
350
100 None
Mild
Moderate
Severe
Fig. 4. Severity of menstrual blood loss at 3 months in women treated with nafarelin or placebo before elective hysterectomy (Ylikorkala, personal communication). p < 0.001 for nafarelin vs placebo by Cochran-Mantel-Haenszel test.
from the Finnish study confirm this effect (Ylikorkala, personal communication). In patients with severe blood loss at baseline, 55% of those randomly assigned to nafarelin therapy had no bleeding at the end of the 3month treatment period compared with 10% of the placebo-treated patients (p < 0.001). In contrast, 48% of patients receiving placebo continued to have severe menstrual bleeding at the end of therapy compared with only 14% of patients receiving nafarelin (Fig. 4). In addition, a mean increase of 4.2% in hemoglobin levels was noted before surgery in patients treated with nafarelin compared with a decrease of 2.7% in the placebo group (p = 0.032). In another study, patients were treated with 3.6 mg of subcutaneous goserelin every 28 days for 6 months. 10 In addition to a reduction in myoma and uterine size, there was a reduction in both menstrual blood loss and blood loss at the time of surgery (Fig. 5). Similar findings were reported in the large leuprolide study.17 In addition to improvement in symptoms in most patients, 37 of 38 patients (97%) with menorrhagia at baseline had resolution by the end of treatment with leuprolide. The decrease in blood loss and the increase in hemoglobin and hematocrit afforded by GnRH agonist therapy have several potential benefits, although it must be emphasized that prospective randomized studies proving these potential benefits have not yet been performed. The patient's hematocrit level may be sufficient to allow the patient to give autologous blood donations before surgery. Further, the lessened perioperative blood loss may reduce the need for blood transfusion and hysterectomy at the time of surgery. Thus the risks associated with blood transfusion, which are often overlooked or underestimated, may be re-
50 0 Uterine Volume
Operative Blood Loss
Fig. 5. Uterine volume and operative blood loss in women with symptomatic uterine fibroids treated for 3 months before elective hysterectomy. p < 0.01 for goserelin vs placebo by Wilcoxon two-sample test. (Modified from Lumsden MA et al. Lancet 1987;1:36-7.)
Table I. Potential advantages of a reduction in uterine and myoma size by GnRH agonists Reduced vascularity • Reduced menorrhagia • Increased hematocrit and iron • Autologous donation • Less operative blood loss • Reduced risk of blood transfusion • Reduced risk of hepatitis Operative technique • Hysterectomy less likely • Operative laparoscopy more likely • Fewer, smaller incisions • Less tissue trauma • Less risk of injury • Pfannenstiel incision more feasible • Vaginal hysterectomy more feasible Integrity of uterine cavity • Hysteroscopic approach • Avoidance of uterine cavity at laparotomy
duced. Between 8% and 18% of patients require blood or blood products at surgery; the current risk of hepatitis is approximately 8% per transfusion. 5 • 18. 19 Other potential advantages from the use of GnRH agonists may result from a reduction of uterine myoma size. These include the use of more conservative surgery; that is, the condition may be managed with myomectomy rather than hysterectomy. Smaller and fewer incisions may result in decreased tissue trauma and increased preservation of normal tissue, possibly reducing adhesion formation after surgery. Other potential advantages are listed in Table I.
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Disadvantages of GnRH agonist therapy Treatment with GnRH agonists is not benign. The known hypoestrogenic side effects are hot flashes and bone loss. About 2% of patients receiving GnRH agonist therapy can experience a very profuse vaginal hemorrhage requiring immediate surgical management. 20 This serious clinical problem has been reported to date only in patients with submucous myomas. The cause of this adverse event is thought to be a reduction in myoma size and a loss of mechanical compression of the vessels within the uterus. Also, painful fibroid degeneration may occur. There is also concern about making the fibroid so small as to avoid detection at the time of surgery. Some investigators have been concerned that myomas may be reduced to an undetectable size by preoperative GnRH agonist use. Results from a recent trial of buserelin before myomectomy suggested that this phenomenon occurs.21 In this randomized trial, a 44% decrease in uterine volume was observed during buserelin therapy in eight patients compared with no change in 16 untreated control patients. Intraoperative blood loss and postoperative morbidity did not differ between groups. However, at the 6-month postoperative evaluation, only 2 of 16 (13%) patients in the untreated group had myomas smaller than 1.5 cm in size compared with 5 of 8 (63%) patients in the buserelin group. These data suggest that small myomas may have been missed at the time of surgery because of preoperative treatment with buserelin. The results of this study need to be confirmed by others, and if true, its clinical relevance established.
Strategies for managing uterine myomas Despite the promising results of studies with GnRH agonists for the treatment of uterine fibroids, surgery remains the treatment of choice. Several different procedures are appropriate including myomectomy by either laparoscopy, laparotomy, or hysteroscopy or hysterectomy by various surgical approaches. However, the use of a GnRH agonist as a preoperative adjunct has some potential benefits to the patient. Preoperative use of GnRH agonists may increase the feasibility of using myomectomy instead of hysterectomy, increase the use of laparoscopic, hysteroscopic, or vaginal procedures, preserve normal uterine tissue, facilitate the operative technique, and reduce blood loss. The choice of therapy will depend on the surgical aspects of treatment, but also on the size and number of myomata, the age of the patient, and the desire to preserve fertility and uterine function. One innovative strategy for managing uterine fibroids with medical therapy only is to combine the GnRH agonist with an estrogen-progestin combination. In a preliminary trial, five women with leiomyomata
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uteri were treated with leuprolide for 24 weeks. 22 After 3 months, conjugated estrogens were added on days I to 25 and medroxyprogesterone acetate from days 16 to 25. Patients were followed for as long as 2 years. A 49% decrease in uterine volume was seen at 3 months, but no further decrease was seen during the next 2 years. There was also a decrease in vasomotor symptoms, and bone density was preserved. These results were encouraging, but additional data obtained on more patients and a longer duration of study have shown a regrowth of the myomas in some patients taking this regimen. This confirms not only that leiomyomata and myometrium are estrogen sensitive, but suggests that an estrogenic threshold exists for uterine growth. It can be seen that different treatment strategies that use GnRH agonists show promise, but the optimal approach to medical treatment of uterine fibroids is unclear. Further studies, many currently ongoing, will help us understand and use GnRH agonists better in the future. In conclusion, results from clinical trials have consistently shown the efficacy of GnRH agonists as a preoperative adjunct for reducing myoma and uterine size and preoperative and perioperative blood loss. Uterine myomas are very sensitive to hormonal changes probably mediated through estrogen and progesterone receptors, the likely mechanism by which GnRH agonists can effect changes. Although the role of the GnRH agonists in the management of uterine leiomyoma has not been fully defined, use as a presurgical adjunct may allow preservation of uterine tissue because of removal of smaller myomas and more conservative surgical procedures.
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