GnRH agonists and uterine leiomyomas - Semantic Scholar · GnRH agonists and uterine leiomyomas state becomes reversed and normal midcycle oestradiol concentrations are produced,

GnRH agonists and uterine leiomyomas

FJ.Broekmans

Department of Obstetrics and Gynecology, Division of Fertility andEndocrinology, Academic Hospital of the University of Utrecht,

Heidelberglaan 100, 3584 CX Utrecht, The Netherlands

Gonadotrophin-releasing hormone (GnRH) agonists are widely used in thetreatment of women with symptomatic leiomyomas. The effectiveness of thistreatment, as far as symptoms are concerned, is well established, and in recentyears many studies have contributed to defining the optimal role for GnRHagonists. Side-effects and health risks prohibit the long-term use of thesecompounds. The combined use of high-dose agonists and steroids in the so-called 'add back' schedules reduces many of the disadvantages of the monother-apy. However, it is still an expensive alternative when compared with definitivesurgery, and therefore should only be used in women who insist on preservationof the uterus. Low-dose agonist therapy ('draw back') has not yet been provento be suitable for clinical application. The use of GnRH agonists and steroids insequential schedules seems to result in a loss of both the volume reduction aswell as the reduction in clinical symptoms. The use of GnRH agonists prior tomyoma surgery should not become a routine measure and should be limited tocases where the size of the uterus is >600 ml. Hysterectomy should only bepreceded by GnRH agonist treatment if uterine volume decrease is expected tofacilitate either the abdominal or vaginal procedure. For both operative proceduresthe presence of myoma-related anaemia is an indication for pretreatment. Theuse of GnRH agonists before endoscopic surgery is widely accepted on the basisof assumptional advantages; however, definite proof of these advantages is notyet available.Key words: GnRH agonists/leiomyoma treatment/pre-treatment/surgery

Introduction

Uterine leiomyomas are very common benign tumours in women of reproductiveage. It is estimated that 20-30% of women have a myoma (Buttram and Reiter,1981). In clinical pathology studies the frequency of myomas is often muchhigher, especially when careful sectioning is applied to hysterectomy specimens(Cramer and Patel, 1990). The myomas can either be single or multiple, mayvary considerably in size and can be found anywhere in the uterine or cervical

Human Reproduction Volume 11 Supplement 3 1996 © European Society for Human Reproduction and Embryology 3

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wall. Size and location of the myomas will determine the symptomatology. Ifsymptoms occur they will fall into one of the following categories: pressuresigns (pain, urinary frequency, constipation), abnormal uterine bleeding (menor-rhagia) and/or reproductive dysfunction (infertility, early pregnancy loss, prema-ture birth, dystocia). Hysterectomy is the classical treatment strategy and theonly definitive cure for myomas. Uterine preservation by abdominal or endoscopicmyomectomy is an alternative, but bears the risk of a repeat surgical approachin case of recurrent myoma growth (Donnez et al, 1989; Candiani et al, 1991;Dubuisson et al, 1991; Verkauf, 1992).

Hormonal therapy aims at reducing symptoms and/or size of the myomas andmay be used either as a long-term treatment or as an adjuvant prior to surgery.Long-term treatment of leiomyomas may be indicated in patients with absolutecontra-indications to surgery or in patients who wish to avoid surgery foremotional reasons or until the menopause takes place. Presurgery uterine andmyoma volume reduction may facilitate both hysterectomy and myomectomyprocedures (Friedman et al., 1989a; Stovall et al, 1991; Falsetti et al, 1992;D'Addato et al, 1992; Vercellini et al, 1993; Lumsden et al, 1994). Gonadotro-phin-releasing hormone (GnRH) agonists are increasingly being used to achievethe aforementioned aims of hormonal treatment.

Mechanism of action of GnRH agonists

Ever since the elucidation of the structure of native GnRH by Schally andGuillemin (see Arimura, 1991), a large number of GnRH analogues have beensynthesized. The agonistic analogues have a higher biological potency thanendogenous GnRH. After binding to the GnRH receptor at the gonadotrophincell surface, an intense release of luteinizing hormone (LH) and follicle stimulatinghormone (FSH) is produced. However, prolonged exposure of the pituitary tothe GnRH agonist results in a desensitization of the gonadotrophin cells withinseveral hours and a rapid decrease in the release and synthesis of gonadotrophins,especially of LH. The gonadotrophin cell will be left unresponsive and depletedas long as the pituitary is continuously exposed to high dosages of the agonist.

In the hormonal treatment of uterine fibroids, the use of i.m. or s.c. GnRHagonist depot formulations has become widespread. In most depots the agonistis dispersed into biodegradable polymer microspheres [poly(DL-lactide-co-glycolide)] (Beck et al, 1979). Plasma concentrations of the agonist during thedelivery period of the depot are related to the total dose of the agonist dispersedin the polymer (Beck et al, 1979; Zorn et al, 1988). Dose studies where theoptimal load of the GnRH agonist is evaluated are almost absent. The singleadministration of a half-dose triptorelin depot (1.87 mg) appears to create aninitial endocrine response which is similar to the one obtained by the full-dosedepot (Balasch et al, 1992). Moreover, the duration of pituitary and ovariansuppression seems to be unaltered by the dose reduction. This may imply that


the amount of agonist present in the standard triptorelin depot is too high toachieve the endocrine and clinical aims.

Most of the depots seem to be designed to release the drug for a 4 weekperiod. However, pharmacokinetic studies after single depot injections are scarse.In two studies the release of triptorelin from the depot in women and men wasstudied (Gonzalez-Barcena et al, 1989; Broekmans et al, 1993). Triptorelinremained detectable until the 7th week after the depot administration. Thisindicates that the interval between depot administrations may well be prolongedto 6 weeks (Broekmans et al, 1993).

Directly after a single GnRH agonist depot administration, a sharp rise isobserved in LH and FSH concentrations. Maximum concentrations are reachedafter 4 h, followed by a gradual decline to subnormal concentrations after 2weeks. LH concentrations remain suppressed below the detection limit of theassays for a period of 7 weeks (Broekmans et al, 1992). FSH concentrationsgenerally show a tendency to be restored to early follicular values. Bioactivityof the circulating FSH appears to be unaltered (Huhtaniemi et al, 1988).

Ovarian function shows an initial response to the gonadotrophin burst, whereoestradiol concentrations become raised to the mid- and sometimes late follicularrange. After 1-2 weeks oestradiol concentrations have fallen to post-menopausalvalues and remain so until the sixth week after the single depot administration.In addition, inhibin concentrations after a single administration of buserelin depotare continuously decreased until ovarian function is restored. Endocrine patternsafter a single administration of goserelin (3.6 mg) or buserelin (3.3 and 6.6 mg)depot show the same short-term effects as after triptorelin depot (Fraser et al,1992). The duration of pituitary and ovarian suppression, however, seems to be2 weeks shorter for goserelin (Matta et al, 1988a) and to be highly variable forbuserelin (Fraser et al, 1992).

Repeated administrations of a GnRH agonist depot formulation will create asolid state of pituitary suppression as evidenced by extremely low LH concentra-tions and absent LH and FSH response to exogenous GnRH bolus injection(Filicori et al, 1993). In addition, repeated administrations will result in acontinued state of hypo-oestrogenism. The degree of ovarian suppression mayshow some slight variation between the different agonist depots (Filicori et al,1993). This may be explained by presumed differences in the degree ofsuppression of FSH and/or LH release by the various depot formulations.

Long-term GnRH agonist treatment in uterine leiomyomas

The first use of a GnRH agonist in the treatment of women with symptomaticleiomyomas was published by Filicori et al (1983). The pituitary desensitizationand ovarian suppression led to a 50% reduction in the volume of the uterus andmyomas and a control of uterine bleeding by creating amenorrhoea. Since then,many studies have been published on the beneficial effects of long-term GnRHagonist treatment in uterine leiomyomas (Maheux et al, 1984, 1987; Healy et al,

FJ.Broekmans

1984, 1986; Coddington et al, 1986; Perl et al, 1987; West et al, 1987; vanLeusden and Dogterom, 1988; Andreyko et al, 1988; Friedman, 1989c; Friedmanet al, 1989b; Golan et al, 1989; Matta et al, 1989; Letterie et al, 1989;Nakamura et al, 1991). Most of the studies in recent years have used depotformulations that release the agonist for several weeks from biodegradablepolymers. Only two studies (Friedman et al, 1989b; Schlaff et al, 1989)have really proved the efficacy of this treatment in randomized, placebo-controlled trials.

After GnRH agonist treatment for 6 months the mean reduction in uterine andmyoma size appears to be 50%, while the response of separate myomas rangesfrom 0-100% (Stewart and Friedman, 1992). The percentage reduction in uterinevolume is negatively correlated with the serum oestradiol concentration duringtreatment and with the patient's body weight (Friedman et al, 1992b). Someauthors have found a positive correlation between the initial fibroid size and thesubsequent regression on therapy (Coddington et al, 1986; Vollenhoven et al,1990). The age of the patient has no predictive value (Vollenhoven et al, 1990;Friedman et al, 1992b). Approximately 85% of the final volume reduction willbe established within the first 2-3 months of treatment (Friedman et al, 1988;Hackenberg et al, 1992; Stewart and Friedman, 1992). Some authors haveclaimed that a poor response to treatment (reduction <50%) can be predicted asearly as after 1 month of treatment (Hackenberg et al, 1992). Related to thereduction in uterine and myoma size, relief in pain and pressure symptoms willbecome clear in the first 2 months (Friedman et al, 1991). By suppression ofthe menstrual cycle, bleeding problems and related anaemia will in most casesbe controlled after the first month of treatment, especially if treatment has beenstarted in the mid-luteal phase of the cycle (Candiani et al, 1990).

When GnRH agonist treatment by monthly depots is discontinued, mensesreturn after an interval of 8-12 weeks. With the return of normal menses, a rapidincrease of the uterine and myoma size is observed towards pretreatment values(Letterie et al, 1989). Even if normal cyclic ovarian function remains suppressedby changing from a monthly agonist depot to a low-dose oestrogen/progesteronecontraceptive pill, a rapid regrowth of the fibroids was observed (Balaschet al, 1995).

Mechanism of GnRH agonist-induced uterine and myoma volumereduction

Continuous exposure of the pituitary creates a state of gonadotrophin desensitiza-tion and ovarian suppression. The subsequent hypo-oestrogenic state is wellcorrelated with the uterine and myoma volume response. If ovarian suppressionis incomplete and oestradiol concentrations do not reach post-menopausalconcentrations initially or the agonist is combined with an oestrogenic substance,reduction in myoma and uterine volume is either absent or minimal (Friedmanet al, 1987; Lumsden et al, 1989b; Uemura et al, 1990). If the hypo-oestrogenic


state becomes reversed and normal midcycle oestradiol concentrations areproduced, rapid regrowth of the uterine fibroids is the result (Letterie et al,1989). Apparently, the role of hypo-oestrogenism is crucial. The mechanism bywhich suppression of oestradiol production leads to uterine and myoma volumereduction, however, is still obscure.

Oestradiol receptor studies have shown that the concentration of this receptoris higher in fibroids treated with a GnRH agonist than in those not treated(Lumsden et al, 1989a; Rein et al, 1990). This paradoxical finding may beexplained by the absence of progesterone, which is known to suppress oestradiolreceptor synthesis (Sherman et al, 1979; Rein et al, 1995). On the other hand,in women exposed for 3 months to tamoxifen, an oestradiol receptor-blockingagent, oestradiol binding in fibroids was significantly lower when compared withnormally-cycling women (Lumsden et al, 1989a). This may indicate that, duringagonist exposure, hypo-oestrogenism leads to a high degree of unoccupiedoestrogen receptors, while up-regulation of receptor numbers by the absence ofprogesterone may be an additional factor. However, receptor studies do notprovide a solid explanation for the fibroid-reducing effects of hypo-oestrogenism.Moreover, the insight into the role of oestradiol and progesterone receptors isfurther blurred by the finding that the combined use of a GnRH agonist andmedroxyprogesterone failed to produce uterine or fibroid volume reduction(Friedman et al, 1988; West et al, 1992).

The role of progesterone suppression by the use of GnRH agonists has recentlybeen reviewed by Rein et al. (1995). Several clinical and biochemical observationssupport the assumption that progesterone may enhance the incidence of somaticmutations in myometrium cells and thereby contribute to myoma formation.Once a myoma has emerged, growth stimulation by progesterone is exerted inthe luteal phase (Harrison-Woolrych and Robinson, 1996). Moreover, progesteroneantagonists have been shown to induce amenorrhoea and significant uterinevolume reduction, while oestradiol concentrations remained at those of the earlyfollicular phase (Murphy et al, 1993). Therefore, the blockade of progesteroneproduction by pituitary suppression may play an important role in addition tothe hypo-oestrogenic state created by the agonist.

Recently, evidence has emerged for the role of local growth factors, includingepidermal growth factor (EGF), that act as mediators of oestrogenic effects onthe myometrium and myoma cells. In a study by Lumsden et al. (1988), thespecific binding of EGF to myoma tissue homogenates was lower after treatmentwith GnRH agonists in comparison with untreated controls.

Oestrogens are known to cause vasodilation of the uterine vasculature, inanimal studies (Resnik et al, 1974; Leiberman et al, 1993) as well as in studiesin the human female (de Ziegler et al, 1991). Doppler assessment of blood flowvelocity wave forms demonstrated a reduction in the blood supply to the uterusduring long-term GnRH agonist treatment (Matta et al, 1988b). Possibly, a hypo-oestrogenism-mediated reduction in the blood flow is the main mechanism ofuterine and myoma volume reduction (Schlaff et al, 1989).

Histologically, fibroids show a high degree of structural variety. They consist

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of elongated smooth muscle fibres and collagenous fibrous tissue. The relativeproportion of these two components is highly variable. Degenerative changessuch as hyalinization, myxoid and cystic changes and calcification furthercontribute to the variability of the histological picture. Therefore, histologicalcomparison of fibroids after long-term GnRH agonist treatment with untreatedfibroids has been difficult. Reports on histology are conflicting. In leuprolide-treated patients, either a reduction in cellularity and proliferative activity(Upadhyaya et al, 1990; Barbieri et al, 1993) or no change at all was observed(Gutmann et al, 1994). In contrast, Rein et al (1993) found significant changesin the extracellular collagen matrix and an increase in the cellularity. Theyconcluded that the reduction in myoma volume could well be the result of areduction in the water content of the cells or the extracellular matrix. Yet anotherreport suggests that tissue necrosis, as a result of ischaemia, is more frequentlyencountered in GnRH agonist pre-treated myomas (Colgan et al, 1993).

Finally, direct effects of the agonist through specific binding sites in leiomyomasmay play an additional role (Wiznitzer et al, 1988), although this has beendoubted by Neuman et al. (1991). Moreover, the use of a GnRH antagonist,which binds to the receptor without intrinsic agonistic effects, has the sameeffect on ovarian oestrogen production and myoma size (Kettel et al, 1993).Recently, a direct effect of GnRH agonists at the level of the granulosa cell hasbeen suggested (Furger et al, 1996), leading to a decrease in the FSH sensitivityof antral follicles and thereby hampering follicular development and oestrogenproduction.

Dose assessment of GnRH agonists in leiomyoma treatment

A few studies have been published indicating that the hypo-oestrogenic state andmyoma volume reduction may well be accomplished by adjustments in the doseschedule. For instance, the use of half-dose leuprolide depots with intervals of 4weeks appeared to have the same effectiveness as the use of full-dose depots(Watanebe et al, 1992). Pharmaco-kinetic and dynamic studies after a singletriptorelin depot administration (Gonzalez-Barcena et al, 1989; Balasch et al,1992) have shown that the depot is capable of suppressing the pituitary andgonad for a period of 6 weeks. Changing the interval between subsequent full-dose depot administrations to 6 weeks may prove to produce the same state ofovarian suppression as with injections at 4 week intervals.

A dose-finding study by Uemura et al (1990) suggested that the use of 900 figof buserelin intranasally may be optimal for adequate reduction in uterine andmyoma volume. The use of 600 u,g had a similar clinical effect but, due tohigher oestradiol concentrations, reduction in myoma volume was almost absent(Smitz et al, 1990). These findings indicate that in the use of GnRH agonistsfor symptomatic or preoperative treatment of women with fibroids data on theoptimal dose are still scarce.

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Side-effects of long-term GnRH agonist treatment

The severe hypo-oestrogenic state induced by the GnRH agonist gives rise toannoying side-effects. Hot flushes are the most prominent side-effect, occurringin >80% of patients. Headaches, depressive mood changes, sleeping disturbances,joint and muscle stiffness, decreased libido, vaginal dryness and dyspareunia andhair loss are reported in 5-15% of cases. In spite of the full pituitary and ovariansuppression, not all women will experience amenorrhoea. Slight, intermittentvaginal bleeding may occur in some 15% of patients and may be explained byendometrial atrophy in an enlarged uterine cavity or by the presence of submucousmyomas. In 2% of all women treated with a GnRH agonist severe haemorrhagedue to necrosis and degeneration of a submucous myoma will appear (Friedman,1989a). Rarely, anaphylactic reactions during the use of the agonist have beenreported (Letterie et al, 1991).

Health risks with regard to cardiovascular changes and accelerated bone lossare additional problems related to long-term GnRH agonist therapy. Studies onplasma lipid profiles have suggested a lipid neutral effect of GnRH agonisttreatment for 6 months (Adashi, 1994). However, continuation of the hypo-oestrogenic state has to result in diminished cardioprotection as has been shownfor the natural menopause (Adashi, 1994). Bone loss at the lumbar vertebraeduring GnRH agonist therapy has been well documented by the use of quantitativecomputer tomography (QCT) and dual energy X-ray absorption (DEXA) andvaries between 2.9-7.4% after 6 months of treatment (Waibel Treber et al, 1989;Whitehouse et al, 1990; Surrey and Judd, 1992; Fogelman, 1992; Dawood,1993; Leather et al, 1993; Scialli et al, 1993; Gallagher, 1993; Uemura et al,1994). The hypo-oestrogenic state is believed to be responsible for the bone loss(Adashi, 1994). Oestrogens have direct effects on bone tissue, presumably byantagonizing osteoclast-mediated bone resorption and stimulating developmentof osteoblastic cells from precursors (Turner et al, 1994). In addition, oestrogensmay directly increase calcium transport by the bowel and kidney (Prince, 1994).After cessation of therapy, recovery of bone density has been claimed to beincomplete (Whitehouse et al, 1990; Surrey and Judd, 1992; Dawood, 1993). Arecent report on long-term effects after a 6 month GnRH agonist treatment perioddocumented a complete recovery of the loss in lumbar bone mineral density 2years later (Paoletti et al, 1996).

Last, but not least, medical treatment of symptomatic leiomyomas may delaythe tissue diagnosis of the rare leiomyosarcoma (Shek et al, 1987; Hitti et al,1991; Murphy and Wallace, 1993; Schwartz et al, 1993). Therefore, an absenceof response to the GnRH agonist therapy must lead to prompt surgical removalof the myomas.

Oestrogenic state correction

Health risks and side-effects make continuation of GnRH agonist treatment for>6 months unattractive. Cessation of therapy leads to restoration of the normal

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250

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wmm- Zone

% Zone

! •̂v v ^ ^ ^ ^ ^ d r - : /:-: • Zone

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Figure 1. Oestradiol threshold hypothesis. Gonadotrophin-releasing hormone (GnRH) agonist treatment willreduce oestradiol concentrations into the post-menopausal range (zone C). By oestrogen and progesterone'add back', oestradiol concentrations are corrected into a threshold area (zone B), in which regrowth of theuterus does not occur and side-effects and bone resorption are limited or prevented (adapted from Friedmanetal, 1990).

menstrual cycle and oestrogenic state, as well as to rapid regrowth of both uterusand individual myomas. As a consequence, clinical symptoms will return inalmost the same pattern as before, although some authors claim that post-treatment symptoms are less when compared with the pretreatment situation (vanLeusden, 1992).

Continuing the GnRH agonist treatment for longer periods only seems possibleif some correction in the gonadal steroid environment is achieved. Friedmanet al (1990) and Maheux et al (1991) have postulated that partial restoration ofthe oestrogenic state in addition to the continued use of the agonist is a possiblestrategy for long-term medical treatment. Oestradiol concentrations within acertain threshold concentration zone would reduce or minimize side effects andprevent ongoing bone loss, without producing regrowth of the myomas (Figure 1).In addition, it has been doubted as to whether a severe hypo-oestrogenic conditionis really necessary to achieve or maintain uterine or myoma volume reduction(Uemura et al, 1990; Maheux et al, 1991).

Partial restoration of the oestrogenic state may be accomplished by administra-tion of small quantities of oestrogen and progesterone in addition to the agonist,after a 3 month period of single agonist therapy (Friedman, 1989b, 1993; Maheuxand Lemay, 1992; Friedman et al, 1993, 1994) (Figure 2). In these so-called'add back' regimens, treatment can be continued for a period of at least 2 years,without regrowth of the uterus. It must be noted, however, that the drop out ratewas rather high in these studies. Furthermore, bone density decreased significantly

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GnRH agonistSteroids

ADD BACKMaheux, 1991

Friedman, 1994

0 3 12 24 MonthsFigure 2. Schematic representation of the sequential 'add back' treatment schedule. Initial gonadotrophin-releasing hormone (GnRH) agonist monotherapy is followed by combined treatment with oestrogen-progesterone (after Stewart and Friedman, 1992).

during the initial steroid-free treatment period, but showed no change during the'add back' period. Sugimoto et al. (1993) demonstrated that the dose of theoestrogen used in the 'add back' scheme may well be crucial in the boneprotecting effects of such regimen, while others showed ongoing bone loss inspite of the steroid 'add back' (Sugimoto et al, 1993; Mezrow et al, 1994).

Periodical complete restoration of endogenous oestrogen production is aanother possible strategy. Intermittent therapy, where a 3 month treatment periodis alternated with a 3 month agonist-free interval, may show minimal increasein uterine size during the drug-free interval (Blumenfeld et al, 1990). Increasingthe interval between subsequent dosages of triptorelin depot from 4 to 10/12weeks seems to create an adequate reduction in uterine volume, while side-effects decreased to such an extent that treatment could be continued for up to2 years (Golan, 1993).

The use of sequential treatment schedules, where GnRH agonist therapy isinterrupted after 3-6 months and is followed by the use of combined oestrogen/progesterone preparations or progesterone alone, has shown that reduction inuterine size is almost completely reversed during the steroid treatment period(Benagiano et al, 1990; Balasch et al, 1995). Apparently, the use of thesesteroid compounds without the concomitant use of GnRH agonists creates amyoma growth promoting situation. This is presumably caused by the lack ofsuppression of endogenous oestradiol production and the use of potent syntheticsteroids, possessing contraceptive properties. It must be noted however, that thisfinding is in contradiction to earlier reports on the reduced risk of myoma growthin women using oral contraceptives (Ross et al, 1986).

Finally, reduction of the agonist dose to a concentration at which endogenousproduction of oestradiol is partially restored without the appearance of highpreovulatory oestradiol concentrations and with continued inhibition of ovulationmay prove to be an adequate treatment modality. Several studies have shownthat the state of pituitary suppression by the agonist is dose-dependent (Monroeet al, 1986; Maheux et al, 1988; Scheele et al, 1996). The degree of pituitarysuppression, induced by a certain dose, appears to remain constant during long-term agonist treatment (Monroe et al, 1986; Maheux et al, 1988; Uemura et al,1992). Ovarian suppression by low-dose agonist treatment has been studied in

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J2Q

8 Weeks 26Figure 3. Schematic representation of the 'draw back' treatment schedule. High-dose agonist therapy for 8weeks is followed by reduced dose treatment in comparison with a continued high-dose regimen.

contraception studies, mainly by Bergquist et al. (Nillius, 1985; Bergquist andLindgren, 1983; Lundkvist and Bergquist, 1986; Gudmundsson et al., 1986,1987). Fluctuating oestradiol concentrations were found without adverse effectson the endometrium, despite lack of progesterone opposition. Treatment waswell tolerated by the patients for long periods of time. These findings indicatethat long-term treatment with low-dose agonist may be an alternative route foroestrogenic state correction.

'Draw back' GnRH agonist treatment of uterine leiomyomas

The possibility of inducing partial correction of endogenous oestradiol productionby reducing the GnRH agonist dose in the long-term treatment of uterineleiomyomas has been investigated in a so-called two-step regimen (Broekmanset al, 1996). Standard, high-dose treatment was followed by reduced dosetherapy. The treatment schedule is depicted in Figure 3. A total of 24 womenwith a uterine size of >300 ml initiated daily s.c. self-administration on thesecond day of the menstrual cycle. A daily dose of 500 (Xg triptorelin was usedfor 1 week, followed by a dose of 100 |xg for 7 weeks. From weeks 9-26,treatment was continued by either 100, 20 or 5 (Xg triptorelin per day.

During triptorelin treatment the median uterine size was reduced to 57.8% ofbaseline (Figure 4). There were no differences in volume reduction between thedose groups. LH and oestradiol concentrations were restored in a dose-dependentway. However, oestradiol concentrations showed considerable variation in thelowest dose group (Figure 4).

From the results in the study it can be assumed that reduction of the agonistload in the triptorelin depot from 3.75 to 1.5 mg may well prove to be adequatein the long-term treatment of women with uterine fibroids, as it will deliver a

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Figure 4. Median (range, middle two quartiles) proportional change in uterine volume (upper panel) andmedian (range, middle two quartiles) steady state lutemizing hormone (LH) and oestradiol concentrations(E2) (middle and lower panel) during standard and randomized dose triptorelin treatment. Steady state LHand oestradiol concentrations were calculated from weekly measurements. P values relate to repeatedmeasurements, analysis of variance with time and dose contrast for linear trends.

daily dose of ~20 u.g of triptorelin. As the delivery from a depot is more constant,compared to the saw-toothed concentrations generated by s.c. injections, evenfurther dose reduction may prove to be possible.

In a study by Gudmundsson et al. (1984), using intranasal, low-dose agonistregimens for contraception, the oestradiol concentrations and bleeding patternsshowed a considerable individual variation, while even in amenorrhoeic womenoestradiol concentrations were in the early follicular range. This implies thatboth the ovarian and endometrium response in the low-dose agonist treatment ishard to predict in an individual patient. The use of a 'draw back' treatmentschedule, where uterine volume reduction is maintained by a low-dose depotformulation and control on the proliferation state of the endometrium is carried

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out by intermittent courses of progesterone is a management strategy that isworth further investigation (Lemay et al, 1985; Geisthoevel et al, 1987).

GnRH agonists and progesterone

The use of progesterone in the treatment of leiomyomas has never been clearlydemonstrated to be successful (Goodman, 1946; Segaloff et al, 1959; Goldzieheret al, 1966). Progesterone, administered in high doses, suppresses the pituitaryrelease of gonadotrophins and thereby blocks the production of oestrogens fromthe ovary. The degree of ovarian suppression, however, appears to be less severewhen compared with GnRH agonist-induced gonadal suppression (Benagianoet al, 1990).

It has become increasingly clear that progesterone has growth stimulatingeffects on leiomyomas (Goldzieher et al, 1966; Rein et al, 1995; Harrison-Woolrych and Robinson, 1996), even in the absence of oestrogens. The combineduse of progesterone and GnRH agonists fails to produce uterine and myomavolume reduction (Friedman et al, 1988; West et al, 1992). When single GnRHagonist treatment for 3 or 6 months is followed by either combined agonist-progesterone therapy (Friedman et al, 1993) or by progesterone alone (Benagianoet al, 1990; Scialli and Jestila, 1996), regrowth of the uterus and myomas isobserved to a considerable extent. Furthermore, the use of progesterone antagonistsas a single therapy has shown to establish a clear volume reduction in womenwith fibroids (Kettel et al, 1994).

Mitotic activity in leiomyomas during the luteal phase often is higher than inthe follicular phase (Kawaguchi et al, 1989). A recent report by Brandon et al.(1993) showed increased expression of progesterone receptor mRNA and proteinin leiomyomas, in comparison with adjacent myometrium. Combined oestrogenand progesterone replacement therapy in post-menopausal women leads to anincreased proliferative index in myomas, whereas oestrogen-only therapy createsproliferation indices comparable to untreated post-menopausal controls (Lam-minen et al, 1992).

GnRH agonist-progesterone therapy may prove to be beneficial with regardto bleeding problems, bone resorption and agonist-related side-effects (Scialliand Jestila, 1996). However, the disadvantages of progesterone-related side-effects, induction of uterine regrowth and less favourable lipid profiles, raisedoubts over whether progesterone will become an acceptable adjunct to theGnRH agonist treatment of leiomyomas.

Pre-surgery GnRH agonist treatment

With the use of GnRH agonists the volume of the uterus can be reduced by 35-50%. The size reduction of myomas seems to be of a lesser magnitude, althougha wide range (15-90%) is reported. With the use of magnetic resonance imaging,

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volume response of myomas is reported to be 30-35%. In addition to sizereduction, blood flow through the uterine vessels is decreased (Matta et al,1988b), presumably caused by the lack of normal oestrogen stimuli on the uterinevasculature (Resnik et al, 1974).

The use of GnRH agonists prior to uterine surgery has been promoted forseveral reasons. A reduction was expected in intraoperative blood loss and inthe need for pre-, per- and postoperative blood transfusions on the basis of sizereduction alone (Ginsburg et al, 1993). Selective removal of fibroids was thoughtto become technically easier, thereby reducing the risk of postoperative formationof adhesions and increasing the fertility potential after preserving surgery. Totalremoval of the enlarged uterus in cases of symptomatic myomas was expectedto become easier, for instance by changing the route of operation from abdominalto vaginal. Finally, application of GnRH agonists before endoscopic fibroidsurgery is promoted for reduction of fluid loss in hysteroscopy and enabling theendoscopic removal of larger fibroids in general. Studies addressing theseexpectations and questions are far from numerous. Comparative studies oftenlack randomization and in the endoscopic field comparison to other hormonal orno pretreatment is absent.

GnRH agonist treatment before abdominal myomectomy

Abdominal myomectomy is indicated in myoma-related menorrhagia and other-wise unexplained infertility of long duration. The means by which myomashamper fertility has been a matter of debate. Impaired gamete transport has oftenbeen suggested but never proven. Cavity distortion by submucous or intramuralmyomas leading to implantation problems is another explanation. Recently, thepresence of cavity deformation has been found to reduce the implantation ratein in-vitro fertilization (IVF) cycles when compared with cases where a normalcavity was seen at hysteroscopy (Fahri et al, 1995). These findings are the firstto really support the assumption that myomas actually impair fertility.

Although the beneficial effects of myomectomy in bleeding problems are wellestablished (Buttram and Reiter, 1981), the role of myomectomy upon fertilitytreatment is still somewhat obscure. A success rate of ~50% within 1 year aftersurgery is achieved in patients with longstanding infertility and no other factorthan uterine myomas (Babknia et al, 1978; Garcia and Tureck, 1984; Rosenfeld,1986; Verkauf, 1992). However, comparative studies providing some definiteproof of benefit are lacking. Finally, conservative surgery on the uterus forfibroids may always be frustrated by an overall recurrence rate of up to 40%(Friedman et al, 1992a; Fedele et al, 1995) and the chance of reducing thefertility potential by postoperative adhesion formation (Tulandi et al, 1993).

The benefits of pretreatment with GnRH agonists for a period of 2-3 monthsbefore myomectomy have been studied by six different authors. Study resultsconcerning blood loss are summarized in Table I. In the placebo-controlled studyby Friedman et al. (1989a), blood loss was assessed by measuring aspirated

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FJ.Broekmans

Table I. Comparative studies on the effect of pre-myomectomy gonadotrophin-releasinghormone (GnRH) agonist (Ag) treatment on intra-operative blood loss and transfusion rate

Author

Randomized, controlledFriedman et al, 1989a

Fedele et al, 1990Golan et al, 1993

Non-randomized studiesFalsetti et al, 1992Gardner and Shaw, 1992Kiltz etal, 1994

n

Ag/no Ag

studies9/95/5

8/1612/9

30/3513/919/9

Mean blood loss (ml)

Ag/no Ag

193/240189/390(uterine size >600 ml)235/275320/476

205/310 0.001304/502650/750

P

NS0.005

NS0.03

_0.01NS

Transfusion rate

Ag/no Ag

22/22

-50/56

—38/5510/30

P

NS

-0.04

-NS

NS = not significant.

blood volume and sponge weight gain divided by 1.06 gm/ml. Myomectomywas performed using a lower uterine segment tourniquet and vascular clamps onthe ovarian vessels. Especially if the preoperative uterine size was >600 ml,blood loss during the actual uterine surgery could be reduced by 50%. Thenumber of patients was, however, small. Fedele et al. (1990) performed anasymmetrical randomized study. The mean pretreatment uterine size was rathersmall (450 ml). No difference in blood loss was reported. This finding may bein line with those of Friedman et al. (1989a), where only the large-sized uterusseemed to benefit from pretreatment. Golan et al. (1993) carried out a randomizedstudy on patients undergoing hysterectomy or myomectomy. Stratification to thetype of surgery was done post hoc. Although the method of assessment of bloodloss was based on estimations of aspirated blood and the number of soaked pads,a clear difference was found in favour of the agonist-treated group. In addition,a significant difference in the need for blood transfusions was reported (Table I).

In the three non-randomized studies historical or matched controls were used.Mean pre-treatment uterine volume was 700 ml in the study by Gardner andShaw (1992), 550 ml in that of Falsetti et al (1992) and 1000 ml in the studyby Kiltz et al. (1994). In the two former studies the difference in blood loss wassignificant. In Gardner's study the very reliable alkaline haematine method wasused for intraoperative blood loss estimation. In the study by Kiltz the use ofthe agonist appeared to have no benefit when compared to the historicalcontrol group.

From the studies presented the benefits of GnRH agonist pretreatment prior toabdominal preserving surgery seem to be confined to cases where the uterinesize exceeds a certain value, for instance 600 ml. Whether these benefits willinclude a reduction in the formation of postoperative adhesions remains to beinvestigated. Finally, there has been some discussion regarding whether pretreat-ment of myomas by GnRH agonists may prevent the identification and removal

16


Table II. Comparative studies on the effect of pre-hysterectomy gonadotrophin-releasinghormone (GnRH) agonist treatment on intra-operative blood loss and transfusion rate

Author

Randomized, controlledStovall et al, 1991Lumsden et al., 1994Golan et al, 1993

Non-randomized studiesVercellini et al, 1993Gardner and Shaw, 1992

n

Ag/no Ag

studies25/2535/3517/15

41/929/11

Mean blood loss (ml)(perop)

Ag/no Ag

527/614187/308208/309

159/333182/350

P

0.0420.0030.03

0.010.01

Transfusion rate(per/postop)

Ag/no Ag

0/5.56/20

0/2011/18

P

NS0.04

0.001-

perop = peroperative; postop = postoperative; NS = not significant.

of smaller myomas. In the study by Fedele et al. (1990), some support for thishypothesis was found from an increased incidence of myoma recurrence in theagonist pretreated group. Friedman et al. (1992a), however, in a study with amuch longer follow-up period, could not confirm these findings.

GnRH agonist treatment before hysterectomy

Hysterectomy for the treatment of symptomatic women with uterine leiomyomasoffers a definite solution. Due to the size of the uterus abdominal surgery isoften mandatory and even with the abdominal approach surgery may not alwaysbe easy. Size reduction of the uterus and reduction in the blood flow in theuterine vasculature by the use of GnRH agonists may improve the handling ofthe uterus and limit the amount of peroperative blood loss and the rate of bloodtransfusions. Preoperative correction of myoma-related anaemia without the needfor blood transfusions may be an additional advantage, although this aim mayin itself be achieved by other hormonal treatments.

Five studies have been published concerning the possible benefits of GnRHagonist pretreatment. Data concerning blood loss are summarized in Table II.Stovall et al. (1991) compared two groups of women in whom the uterine sizewas between 14-18 weeks' gestation. Patients in the group pretreated withleuprolide acetate for 2 months were much more likely to undergo a vaginalhysterectomy (76 versus 16%). The small difference in the peroperative bloodloss in favour of the pretreated group may be explained by the difference betweenthe groups in the route of operation. In the very detailed study by Lumsden et al.(1994), a clear difference was found in the amount of peroperative blood loss,while hysterectomy in the agonist-treated group was technically easier. Inaddition, pretreatment with the agonist allowed a transverse incision in 69% ofcases compared with 44% in the placebo treated group. In the study by Golanet al. (1993), in addition to the reduction in blood loss during surgery, operating

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RJ.Broekmans

time was significantly reduced. This finding, however, is not confirmed in theother studies.

In a non-randomized trial, Vercellini et al. (1993) analysed the effects ofpretreatment in patients with myoma-associated menorrhagia. It was shown thatin the pretreated group the vaginal route of operation could be chosen threetimes as often as in the nontreated group, while the pretreatment uterine sizewas not different between the groups. In the control group the need forpreoperative blood transfusions was ~35%, compared with zero for the agonist-treated group. Finally, the study by Gardner and Shaw (1992) showed a differencein the amount of blood loss in favour of the agonist-treated group. However, theinitial uterine size was clearly greater in the control group, which may accountfor the observed differences.

In two additional reports the possible benefits of agonist pretreatment werestudied in mixed groups of patients, comprising myomectomy and hysterectomycases (Audebert et al, 1994), or patients with either myomas or a normal uterus(Ylikorkala et al, 1995). These studies, therefore, could not be included in oneof the tables. In the study by Audebert, the main benefit from pretreatment wasin a reduction of the need for blood transfusions and a possible faster and safersurgical procedure. Ylikorkala concluded that GnRH agonist pretreatment isindicated if preoperative anaemia needs correction.

The advantages of GnRH agonist pretreatment in hysterectomy proceduresseem to be more clearly defined than in abdominal myomectomy. However, thebenefits may not outweigh the costs related to the use of these hormones andtherefore preoperative treatment should not be recommended as a routine measure.The use of these compounds may be indicated in cases where the uterine sizereduction is expected to enable the use of a transverse incision or vaginal routeof operation. For preoperative correction of myoma-associated anaemia, a GnRHagonist should only be used if there is an indication for uterine size reduction assuch. In any other case, suppression of the pituitary-ovarian axis can be achievedby much cheaper hormone preparations.

GnRH agonist treatment before endoscopic myomectomy

The use of GnRH agonists prior to endoscopic surgery results in a reduction ofthe blood flow in the uterine vasculature (Matta et al, 1988b), a decrease in sizeof the myomas, and a reduction in size of the uterine cavity (Watanabe andNakamura, 1995). Furthermore, the ovarian suppression leads to endometrialatrophy. These changes induced by the agonist are believed to reduce the amountof blood loss during endoscopic surgery, facilitate surgery on larger myomas,and diminish the risk of distension fluid loss into the circulation. The use ofagonists is widely advocated (Donnez et al., 1989; Dubuisson et al, 1991), inspite of the fact that proper comparative studies are lacking. The preoperativetreatment with progesterone preparations in order to induce endometrial atrophymay be an alternative and cheaper strategy, which deserves comparison to GnRH

18


agonists with regard to intraoperative blood loss, technical ease and fluid balance.As stated earlier, the possibility of gestagen-induced increase in myoma volumehas recently been stressed by several authors (Rein et al., 1995; Harrison-Woolrych and Robinson, 1996).

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GnRH agonists and uterine leiomyomas - Semantic Scholar · GnRH agonists and uterine leiomyomas state becomes reversed and normal midcycle oestradiol concentrations are produced,