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5th World Congress on Controversies in Obstetrics, Gynecology and Infertility
GnRH Analogue Therapies Prior to Myomectomy/Hysterectomy
Jacqueline N. Gutmann, M.D.
Stephen L. Corson, M.D.
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Uterine leiomyomata, also known as fibroids or myomas, are the most
common pelvic tumor, found in at least 20-25% of women by the age of 35 (1) and
more than 50% of all women (2). Though the majority of fibroids (50-80%) are
asymptomatic, they can be the cause of pelvic pressure and pain, excessive
menstrual bleeding, spontaneous abortion and infertility. The standard treatment for
symptomatic myomas has been surgical; approximately 40% of abdominal
hysterectomies are performed for the treatment of myomas (3). In those women
who wish to preserve fertility, myomectomy is performed.
Though the pathogenesis of uterine myomas is not well understood, it is
known that these tumors are steroid responsive. Myomas are rarely present prior
to menarche and typically regress after menopause when sex steroid levels are low.
Estrogen and progesterone receptors are present in myoma tissue (4). In addition,
there is pathologic and biochemical evidence that the sex steroids have a greater
impact on myoma tissue or normal myometrium. Estrogen and progesterone
receptors appear to be over expressed in myoma tissue compared with normal
myometrium (5).
It follows that medications that reduce the levels of gonadal steroids are
options for the treatment of uterine myomas. Though oral contraceptives and
progestins have been demonstrated to reduce menstrual blood loss, they have not
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been shown consistently to cause myoma shrinkage. The use of a gonadotropin
releasing hormone agonist (GnRH-a) in a woman with uterine myomas was first
reported by Filicori in 1983 (6). This patient experienced a 77% reduction in
myoma volume, cessation of excessive bleeding and an increase in hemoglobin
concentration from 7.4 to 12.8 g/dL.
Since the initial report, multiple uncontrolled studies have demonstrated the
efficacy of GnRH-a in the reduction of uterine volume, resolution of anemia and the
induction of amenorrhea. The reported reduction of uterine volume with the use of
a GnRH-a ranges between 35 and 65% (7-12). The response of an individual
fibroid is more difficult to predict secondary to the heterogeneity of myoma
composition (7). A number of randomized, double-blind, placebo-controlled trials
confirmed the efficacy of GnRH-a in achieving reduction of uterine volume and
improvement in symptoms (13-16). In the largest of these trials, the use of
leuprolide acetate (LA) was associated with a reduction in mean uterine volume of
36% and 45% after 12 and 24 weeks of therapy, respectively (Figure 1)(14).
Patients treated with placebo had increases in mean uterine volume of 16% after 12
weeks and 5% after 24 weeks. Seventy-seven percent of LA treated patients had
more than 25% reduction in uterine volume. The majority of patients had resolution
or improvement of their myoma related symptoms after 24 weeks of LA treatment.
All clinically available GnRH-a are capable of producing profound pituitary and
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gonadal suppression. Hence, they should all be beneficial in the treatment of uterine
myoma. Studies evaluating buserelin, histrelin, gosarelin, nafarelin and decapeptyl
have all demonstrated reduction in uterine volume and symptoms (7-12). A small
randomized trial comparing intranasal buserelin with subcutaneous gosarelin found
no difference in the percentage of patients who responded to therapy (17). Though
inadequate pituitary/gonadal suppression may reduce the efficacy of GnRH-a, it
does not appear that increasing the dose results in a greater effect on myoma size.
Watanabe reported that administration of 1.88 mg of LA resulted in an equivalent
reduction in uterine volume as 3.75 mg LA (41% and 45%, respectively)(18). Others
have found that monthly doses greater than 3.75mg LA did not result in a decrease
in the size of the myoma (19). Maximum reduction in uterine size typically occurs
within the first three months of therapy with minimal additional benefit derived from
additional treatment (Figure 1)(9,11,14). Larger fibroids appear to experience a
greater reduction in size than smaller ones (20,21).
The safety and side effect profile of GnRH-a administration is related to the
induced hypoestrogenic state. Over 90% of women treated with GnRH-a
experience vasomotor symptoms (12). Approximately half will also experience
insomnia, mood swings, headaches and vaginal dryness (12). In a large study, all
women treated experienced at least one symptom, but only 6% of women
discontinued therapy because of adverse effects. The presence of hot flushes did
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correlate with estradiol (E2) levels. Ninety-eight percent of patients with E2 levels
less than or equal to 30 pg/mL experienced hot flushes as compared with only 50%
if the level was greater than 30 pg/mL. A potential risk of hypoestrogenism is bone
loss. Though treatment with up to 6 months of GnRH-a is associated with increased
bone turnover (15), it does not appear that clinically significant bone loss occurs
with short term therapy (14).
The addition of sex steroids to GnRH-a therapy was investigated as a means
to allow for prolonged GnRH-a therapy while ameliorating side effects including
vasomotor symptoms and hot flushes. A number of "add-back" protocols have been
investigated, most commonly unopposed GnRH-a for 12 weeks followed by
continued GnRH-a administration with either progestin alone or an
estrogen/progestin combination. Superimposition of an estrogen/progestin regimen
appears to be the most efficacious as it alleviates hypoestrogenic symptoms,
prevents bone loss and does not reverse the salutary effects of the GnRH-a (Figure
2)(23).
Unfortunately, after cessation of GnRH-a therapy, there is rapid regrowth of
myomas in the majority of patients (Figure 1)(9-14,17). Mean uterine volume
typically approaches pretreatment values within 6 months of discontinuing therapy
(14). This limits the use of GnRH-a as a primary therapy for uterine myomas. An
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exception to this is the use of GnRH-a in women who are approaching menopause.
In this situation, GnRH-a may be efficacious as a temporizing measure; i.e. reducing
uterine volume and controlling bleeding until natural menopause ensues (24).
Because therapy with GnRH-a results in a decrease in uterine size,
amenorrhea and resolution of anemia, it has been used in preparation for definitive
surgical therapy. It was postulated that the temporary reduction of uterine volume
might facilitate conversion of an abdominal into a vaginal hysterectomy or allow for
a transverse rather than a longitudinal incision. Other potential advantages of
pretreatment were thought to include decreased operative time, reduction in blood
loss and postoperative morbidity in patients undergoing hysterectomy or
myomectomy.
A recent Cochran review evaluated the role of pretreatment with GnRH-a
prior to hysterectomy or myomectomy for uterine myomas (21). The review
included 14 randomized controlled trials where GnRH-a was compared with no
pretreatment (1005 patients) and six trials (825 patients) where GnRH-a treatment
was compared with placebo. Results for preoperative outcomes were combined for
hysterectomy and myomectomy but results for intra and postoperative outcomes
were reported separately for each type of surgery. Despite the vast amount of data
evaluated in this review, it is not without limitations. The authors utilize
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sophisticated statistical analyses to overcome some of the difficulties encountered
in any meta analysis. However, it is difficult to control for all of the variables that
could impact outcome including use of different types of GnRH-a, route of
administration, duration of therapy, methodology utilized to measure uterine/myoma
volume and skill of the surgeon.
As with the earlier studies, the Cochran review found the GnRH-a therapy
resulted in a significant increase in preoperative hemoglobin and hematocrit.
Uterine and myoma volume were significantly reduced. Symptoms attributable to the
myomas were ameliorated with treatment (21).
The impact of GnRH-a on intraoperative outcomes is less clear. Doppler
ultrasound has demonstrated that use of GnRH-a results in a significant reduction of
blood flow to the myoma and uterus (25). It was postulated that this could be
associated with less intraoperative bleeding.
There was only one placebo
controlled trial evaluating intraoperative blood loss during myomectomy and this
found no difference between the two groups. Blood loss was reduced in the
myomectomy trials in which GnRH was compared with no treatment (-67 mL).
Blood loss was also reduced in the GnRH-a treated group in both types of trials for
hysterectomy (-58 mL). These reductions in intraoperative blood loss were
associated with a small improvement in postoperative hemoglobin and hematocrit,
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but were of minimal clinical importance. No difference in the rate of transfusion
was noted in any of the groups (21). Trials published after completion of the
Cochran review evaluating preoperative GnRH-a therapy also found a slight
reduction in intraoperative blood loss (26-28). One patient who did not receive
GnRH-a therapy required transfusion (26).
There are few data evaluating the ease of surgical extirpation. A recent trial
found no difference in the degree of surgical difficulty as reported by the operator
(27). In addition, they found that ease of identification of surgical planes was also
not different between treated and untreated subjects. It has been suggested that
though the smaller size of the myoma may facilitate surgery, changes induced by
GnRH-a may make myomectomy more difficult.
In support of this hypothesis,
Deligdisch found significant histopathologic changes including hyaline degeneration
representing a scar-like retraction and obliteration of the interface between the
myoma and myometrium in specimens from patients treated with GnRH-a (29).
Others, however, have not identified consistent histopathologic changes associated
with GnRH-a administration (30). To date, the question as to whether GnRH-a
makes the process of "shelling out" myomata more difficult has not been adequately
addressed.
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Operating time has, in part, been used as a surrogate for surgical difficulty.
The studies included in the Cochrane review did not find a difference in duration of
surgery in analogue-treated patients undergoing myomectomy compared with the
control group (21). An additional trial also evaluating abdominal myomectomy failed
to find a difference in operating time (27). Interestingly, a study in which patients
were undergoing laparoscopic myomectomy did find a reduction in duration of
surgery in the treated group when compared with placebo (91.5 + 17.6 and 117.3 +
16.1 minutes, respectively)(26).
Five studies evaluated surgical difficulty during hysterectomy (21). A higher
rate of difficult surgery was found in the placebo group when compared with the
GnRH-a treated group, though the beneficial effect appears to be small. In a small
study evaluating the use of GnRH-a prior to laparoscopic hysterectomy for large
uteri (16-20 weeks gestation), the need to convert to laparotomy occurred in 3 of 8
women in the control group and none in the treated group (28). In this population,
mean operating time was reduced by 26% in the treated group. The Cochrane
review also found a reduced operating time in the patients treated with GnRH-a.
The benefit, however, was only about 5 minutes or under 10% of the total operating
time (21).
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One myomectomy study evaluated the likelihood of vertical skin incision and
found that it was reduced in women treated with GnRH-a when compared to
controls (21). In this study, the surgeon was blinded to treatment allocation. In
hysterectomy studies, the choice of surgical approach (vaginal vs. abdominal) and
type of incision (vertical vs. transverse) were altered favorably with the use of
GnRH-a (21). The surgeon was blinded in some but not all of the studies. In one
study, GnRH-a pretreated patients were stratified into two groups based on uterine
size. Patients whose pretreatment uterine size was 14-18 weeks gestation were
more likely to undergo vaginal hysterectomy than the control population. No
difference was seen in those patients whose pretreatment uterine size was greater
than 18 weeks gestation (31).
In general, postoperative complication rates for hysterectomy and
myomectomy were low. In the Cochrane analysis, GnRH-a treatment did not
impact the risk of postoperative complications in patients undergoing myomectomy.
The likelihood of postoperative complications was decreased for GnRH-a patients
after hysterectomy (OR=0.62, 95% CI 0.4-0.97)(21). A recent trial evaluating
GnRH-a pretreatment in patients with large uteri undergoing laparoscopic
hysterectomy also found a significant decrease in postoperative complications in the
treated patients (28). Though postoperative hemoglobin was higher in the GnRH-a
treated groups in patients undergoing myomectomy and hysterectomy, the
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difference was less than 1 g/dL, with mean hemoglobin levels greater than 10 g/dL
in all populations (21). The duration of hospital stay after myomectomy was not
affected by GnRH-a treatment (one study)(21). Similarly, a recent trial failed to find
a difference in the duration of hospitalization (21). The duration of stay was
reduced in treated patients undergoing hysterectomy
(-1.1days, 95% CI -1.2
- -0.9)(21).
It has been suggested that the use of GnRH-a will make small myomas even
smaller thereby increasing the likelihood that they would be overlooked at the time
of myomectomy. A small unblinded study showed an increased risk of myoma
recurrence in women pretreated with GnRH-a. Conversely, a small blinded trial
found no association between the use of GnRH-a preoperatively and myoma
recurrence (21). The limited data available precludes providing an answer to this
question.
A small study found that pretreatment with GnRH-a was associated with a
decrease in plasminogen activator (PA) inhibitor but no change in PA level,
suggesting increased fibrinolytic capacity in peritoneal fluid obtained from GnRH-a
treated patients. Follow-up surgery (either at laparoscopy or cesarean section)
found lower adhesion scores in the treated group (32). This finding, which needs to
be confirmed in larger, blinded trials, suggests that fertility may be improved
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through a decrease in adhesion formation by GnRH-a administration prior to
myomectomy. A small study found no difference in cumulative pregnancy rate
between those who received GnRH-a treatment prior to myomectomy and those
who did not (21).
The use of GnRH-a appears to be associated with an increase in the
likelihood of vaginal rather than abdominal hysterectomy and horizontal rather than
vertical skin incision. Typically, vaginal hysterectomy and laparotomy with
horizontal rather than vertical incisions are less costly procedures. This prompted
the evaluation of the cost effectiveness of preoperative GnRH-a. Models were
constructed using available clinical data. One study concluded that the benefits of
conversation to the vaginal route, or horizontal incision for either myomectomy or
hysterectomy, did not justify the costs (33). Another study found that the use of
preoperative GnRH-a therapy before hysterectomy for patients with uterine size
equivalent to 14-18 weeks gestation represents a significant cost saving alternative
(34).
Over the past decade, the use of hysteroscopy in the treatment of submucosal
myomas has increased. Presurgical treatment with GnRH-a can be expected to
result in a reduction in myoma size and correction of anemia. Additional benefits of
pretreatment with GnRH-a includes the induction of endometrial atrophy, which
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should improve hysteroscopic visibility and reduction of uterine blood flow leading
to a decrease in operative bleeding. Unfortunately, there are limited prospective
controlled data evaluating the efficacy of GnRH-a treatment prior to hysteroscopic
resection. Donnez reported that pretreatment with GnRH-a was associated with a
decrease in fluid absorption during hysteroscopic myomectomy (330 mL vs. 750
mL)(35). Pretreatment with GnRH-a was also associated with a reduction in
operating time (25 min vs. 37 min), intraoperative bleeding and amount of distention
medium required (36). The degree to which these benefits have significant clinical
importance is uncertain. Pretreatment with GnRH-a is certainly helpful in the
resolution of preoperative anemia and perhaps in facilitating hysteroscopic resection
of large submucosal myomas.
Use of adjuvant GnRH-a is not without risk. There have been case reports of
patients, particularly those with submucosal lesions, presenting with profuse vaginal
bleeding several weeks after initiation of therapy. Treatment with high dose
combination estrogen/progestin was successful in achieving amenorrhea and
surgical extirpation was possible (37). There is also the potential of GnRH-a
therapy resulting in a delay of the surgical treatment of an unsuspected
leiomyosarcoma (38). Although rare, the worsening of vaginal bleeding and failure
of the myomas to respond to GnRH-a should prompt further evaluation.
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Pretreatment with GnRH-a prior to hysterectomy or myomectomy for uterine
myomas appears to be beneficial in selected circumstances (Table 1). The greatest
advantage may be seen in patients undergoing laparoscopic and hysteroscopic
procedures. There also are potential disadvantages associated with preoperative
GnRH-a therapy (Table 2). The benefits of preoperative GnR`H-a therapy seem to
outweigh the risks for most individuals. Patients most likely to derive the greatest
benefit are those who are anemic or with large uteri. The benefits seem to be
greater for those patients undergoing hysterectomy rather than myomectomy.
Finally, though the data are sparse, it appears that those patients undergoing
endoscopic procedures also are likely to derive benefit.
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