Treatment of uterine leiomyomas with luteinizing hormone-releasing ...

Human Reproduction vol.12 no.9 pp.2028–2035, 1997

Treatment of uterine leiomyomas with luteinizing hormone-releasing hormone antagonist Cetrorelix

David Gonzalez-Barcena1,4, Raquel Ban˜uelos Alvarez1, Elizabeth Pere Ochoa1, Imelda Cardenas Cornejo1, Ana M.Comaru-Schally2, Andrew V.Schally2, Juergen Engel3, Thomas Reissmann3 and Hilde Riethmu¨ller-Winzen3

results support the use of Cetrorelix for the management of uterine leiomyomas. Key words: Cetrorelix/hysterectomy/LH-RH antagonist/uterine leiomyomas

1The

Introduction Uterine leiomyomas (fibroids) represent the most common solid pelvic tumours and are associated with abnormal uterine bleeding and infertility. Myomas arise in 25–30% of women during the reproductive years and constitute a frequent indication for hysterectomy (Buttram and Reiter, 1981; Cramer et al., 1985; Tamaya et al., 1985). Myomas are oestrogen-dependent, rarely seen before puberty and their progression stops after menopause (Buttram and Reiter, 1981; Cramer et al., 1985; Tamaya et al., 1985; Santoro et al., 1996). Induction of oestrogen deprivation by chronic administration of luteinizing hormone-releasing hormone (LH-RH) agonists can be used for medical management of leiomyomas in pre-menopausal women (Filicori et al., 1983; Healy et al., 1984; Coddington et al., 1986; van Leusden and Dogterom 1988; Friedman et al., 1989, 1990, 1991; George et al., 1989; Letterie et al., 1989; Lumsden et al., 1987; Neves-e-Castro and Correia, 1987; Perl et al., 1987; Schally 1989; Schally et al., 1993; Lemay et al., 1994; Ayala et al., 1995). However, cessation of therapy with LHRH agonists and return to ovulatory menstruation are generally accompanied by rapid regrowth of fibroids (Lumsden et al., 1987). Moreover, pituitary desensitization, hypo-oestrogenism and shrinkage of uterine fibroids or reduction in uterine volume may be achieved in most patients only after 4–8 weeks of administration of LH-RH agonists (Healy et al., 1984; Coddington et al., 1986; Lumsden et al., 1987; Neves-e-Castro and Correia 1987; Letterie et al., 1989). LH-RH antagonists act more rapidly than the agonists, produce an immediate inhibition of pituitary–gonadal axis, avoiding an initial gonadotrophin and sex-steroid stimulation and exacerbation of hormone-sensitive disease (Schally, 1989; Schally et al., 1993). Early antagonistic analogues of LH-RH had a relatively low potency, and large doses were needed to suppress gonadotrophin concentrations and the response to exogenous LH-RH (Gonzalez-Barcena et al., 1977; Schally, 1989; Schally et al., 1993). The subsequent generation of LH-RH antagonists with D-arginine or other basic residues in position 6 had improved activity, but produced side-effects due to histamine release (Schally 1989; Schally et al., 1993). Development of modern LH-RH antagonists with reduced allergenic side-effects (Bajusz et al., 1988; Schally 1989; Schally et al., 1993) made possible various clinical studies (Behre et al., 1992; Klingmuller et al.,

Hospital de Especialidades Centro Me´dico La Raza – IMSS, Mexico, 2The Endocrine, Polypeptide and Cancer Institute, Veterans Affairs Medical Center and Tulane University School of Medicine, New Orleans, Louisiana, USA and 3ASTA Medica A.G., Frankfurt am Main, Germany 4To

whom correspondence should be addressed at: Instituto Mexicano del Seguro Social, Hospital de Especialidades Centro Medico La Raza, Departamento Clinico de Endocrinologia, Seris Y Zaachila, Col., La Raza, Mexico, D.F. 02990

The efficacy of the luteinizing hormone-releasing hormone antagonist Cetrorelix (SB-75) in the medical management of uterine leiomyomas (fibromas) was evaluated. Cetrorelix was administered to 18 pre-menopausal women with myomas with a mean age of 33.3 years, who had been candidates for hysterectomy. The initial dose of Cetrorelix was 5 mg twice daily s.c. for the first 2 days and thereafter 0.8 mg was given twice daily s.c. for at least 3 months. The mean duration of the treatment was 4.4 months. Before the therapy with Cetrorelix, the mean uterine volume, measured by ultrasonography, was 395.4 6 69.2 ml (range 89–1166). Sixteen patients showed a progressive reduction in uterine volume from 410.4 6 77.1 to a mean of 230.8 6 52.6 ml at 3 months. All patients became amenorrhoeic and had hot flushes. After treatment with Cetrorelix, a surgical myomectomy was performed in 12 women. One of the patients subjected to myomectomy after therapy with Cetrorelix became pregnant. These patients have been followed for up to 25 months and only in one case has the uterine volume increased after therapy. Three patients had good responses to therapy with Cetrorelix and it was decided to follow them only by observation. One patient became pregnant 2 months later. In the other patient, the uterine volume remained unchanged for the duration of the follow-up of 2 years and the third patient showed an increase after 21 months. In three patients, it was necessary to perform total hysterectomy. In 14 patients, serum concentrations of luteinizing hormone, follicle stimulating hormone and oestradiol decreased after the administration of the first dose of Cetrorelix and continued at subnormal values throughout therapy. In 15 patients who were not subjected to total hysterectomy, menstrual function returned at 1 month after cessation of treatment. Overall 2028

© European Society for Human Reproduction and Embryology

Cetrorelix therapy for leiomyomas

1993; Reissmann et al., 1994; Gonzalez-Barcena et al., 1994a,b, 1995). Among these new LH-RH antagonists [Ac-DNal(2)1,D-Phe(4Cl)2,D-Pal(3)3, D-Cit6, D-Ala10] LH-RH (Cetrorelix, SB-75) was shown to be one of the most powerful (Schally 1989; Behre et al., 1992; Klingmuller et al., 1993; Schally et al., 1993; Gonzalez-Barcena et al., 1994a,b, 1995; Reissmann et al., 1994). Cetrorelix is essentially free of allergenic effects (Schally, 1989; Klingmuller et al., 1993; Schally et al., 1993; Reissmann et al., 1994), more potent than other LH-RH antagonists such as Nal-Glu or Detirelix (Klingmuller et al., 1993) and even in large doses only occasionally causes minimal erythema in contrast to Nal-Glu antagonist, which produces local side-effects (Behre et al., 1992). Recently, Kettel et al. (1993) showed regression of uterine leiomyomas after administration of Nal-Glu antagonist. The responses to Cetrorelix have been previously evaluated in normal men (Behre et al., 1992; Klingmuller et al., 1993; Gonalez-Barcena et al., 1994b), post-menopausal women (Gonzalez-Barcena et al., 1994a), and patients with benign prostatic hyperplasia, and advanced prostatic cancer (GonzalezBarcena et al., 1994a; 1995). Cetrorelix has also been used to prevent premature LH surges in women undergoing in-vitro fertilization (IVF) and embryo transfer procedures (Olivennes et al., 1994; Reissmann et al., 1995). In view of favourable clinical results, we decided to evaluate the response to Cetrorelix in 18 women with symptomatic uterine leiomyomas, who had been candidates for hysterectomy.

Materials and methods Eighteen pre-menopausal women, between 21 and 47 years of age (mean 6 SD; 33.3 6 1.49), who had been candidates for hysterectomy due to excessive uterine bleeding or enlarged uterine leiomyomas, volunteered for this study. All of them were menstruating with cycle lengths between 15 and 30 days (mean 5 25.4 6 0.8). Ten women complained of menorrhagia and four of menometrorrhagia. The mean number of previous pregnancies was 0.94 6 0.38 (range 0–7), delivery 0.77 6 0.28 (range 0–5) and 14 women still desired to become pregnant. Their mean body mass index was 25.6 6 0.7 kg/m2 (range 21.3–31.8). None of the women had used any hormonal medication before beginning the study. Baseline ultrasound examinations of uterine volume were obtained with a General Electric model RT 3000, sectorial transductor 3.5 and 5.0 MHz before treatment and were repeated at 3 months. Uterine volume examinations were also carried out in 13 patients at 1 month and in 11 patients after a longer follow-up. This study was conducted as an open label clinical trial. The patients were admitted to the Endocrinology Department of the Hospital de Especialidades, Centro Me´dico La Raza, Mexico, D. F. Informed consent was obtained from all women after the therapeutic options available had been explained. The study was approved by the Hospital Ethics and Scientific Research Committee (protocol number 94-690-0329). The LH-RH antagonist Cetrorelix [Ac-D-Nal(2)1,D-Phe(4Cl)2,DPal(3)3, D-Cit6, D-Ala10] LH-RH was synthesized and provided by ASTA Medica (Frankfurt/M, Germany). The analogue was dissolved in 5% mannitol solution and sterilized in an autoclave for 15 min at 1.25 kg/cm2 and 120°C. For the injection, each dose was diluted to 1 ml and administered by the s.c. route. Initially a loading dose of 5 mg Cetrorelix was given every 12 h for 2 days and then a

maintenance dose of 0.8 mg was administered twice daily for at least 3 months. The mean duration of the treatment based on 18 patients was 4.4 6 0.4 months (range 3–10). However, since case no. 6 was treated for 10 months because of the lack of response and case no. 3 received Cetrorelix for 8 months due to a delayed response, the mean duration of treatment of the remaining 16 patients was only 3.8 months (range 3–5 months). Each patient was considered as her own control. For hormonal evaluation, an indwelling i.v. catheter was placed in the antecubital fossa vein. Blood samples were taken the day before the first injection of Cetrorelix (day 0). The administration of Cetrorelix was initiated on day 1. Blood samples were taken every 3 h for up to 9 h on days 1, 3 and 5 and subsequently every month immediately before the administration of Cetrorelix and 6 h later. After centrifugation, serum was separated and frozen for radioimmunoassays. Radioimmunoassay kits for LH, follicle stimulating hormone (FSH) and oestradiol were obtained from CISBiointernational (Paris, France). The gonadotrophin results are expressed as international units of the second international reference preparation of human menopausal gonadotrophin. The intra-assay and interassay variations were ,9%. The compliance with the medication was assessed by the number of vials of Cetrorelix dispensed and returned and the replacement doses of the antagonist every 2 weeks. Statistics Unless otherwise indicated, all values were expressed as the mean 6 SEM. Statistical significance was calculated by Student’s paired t-test.

Results Seventeen patients had intramural myomas and one patient (case no. 13) a myoma with a pedicle and an initial volume of 99.7 ml. Sixteen patients showed a progressive decrease of uterine volume in response to Cetrorelix and in 13 of them the reduction was evident after the first month of therapy (Table I). Before the start of therapy with Cetrorelix, the mean uterine volume of these 16 patients was 410.4 6 77.0 ml (range 99.7–1166.0), and after 3 months of therapy it decreased to 230.8 6 52.6 ml (range 30.0–735.8) (45% reduction). Figure 1 shows the change in the uterine volume at 3 months of the 18 patients who were treated with the continuous administration of Cetrorelix. Not all the uterine volumes decreased to the same degree. One patient (case no. 3) responded with a delayed decrease, the volume at 3 months being practically unchanged, but after 8 months of continuous therapy the uterine volume decreased from 314.3 to 239.3 ml (24% reduction). In nine patients who were treated for .3 months, the mean final uterine volume was 215.9 6 77.5 ml (range 39–843.6). One patient (case no. 6) did not respond in spite of 10 months of therapy. Table I shows the clinical profiles, the fertility antecedents, the menstrual pattern, the desire to become pregnant and individual changes in the uterine volume during and after the therapy with Cetrorelix. The fourteen patients with a mean age of 30.7 6 1.1 years, who still desired to become pregnant (nos. 1–14), had greater baseline uterine volumes with a mean of 447.8 6 88.5 ml, which at 3 months decreased to 269.4 6 56.6 ml (39.8% reduction) in response to Cetrorelix. On the other hand, four patients (nos. 15–18) with a mean age of 42.2 6 2 years, who had their parity 2029

D.Gonzalez-Barcena et al.

Table I. Clinical profiles, fertility antecedents, menstrual patterns, desire to become pregnant and uterine volume before and during therapy with the luteinizing hormone-releasing hormone antagonist Cetrorelix (SB-75) in 18 patients with leiomyomas who were candidates for hysterectomy Case no.

Age (years)

Pregnancy/ delivery

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18

21 25 27 9 30 30 31 31 32 33 34 35 36 37 37 40 45 47

0/0a

Mean 6 SE

33.33 6 1.49

1/1a 1/1a 0/0a 0/0a 0/0a 1/1a 1/1a 0/0a 0/0a 0/0a 1/1a 0/0a 1/1a 2/2 0/0 2/2 7/5

Menstrual cycle

Uterine volume (ml)

Lengths

Pattern

Initial

1 month

3 months

Final

22–3038 15–3036 2836 3033 2837 2835 23–2533 20–2236–7 28315–30 2836 2533 24–2833 2535 2136–8 2837 2838 15310 2738

Menorrhagia Menometrorrhagia Menorrhagia Normal Menorrhagia Menorrhagia Normal Menometrorrhagia Menorrhagia Menorrhagia Menorrhagia Normal Normal Menometrorrhagia Menorrhoea Menorrhagia Menometrorrhagia Menorrhagia

757.24 942.92 314.35 640.18 337.14 237.21 297.85 601.32 141.09 1166.01 353.61 222.95 99.72 158.72 248.88 236.28 226.25 136.53

459.15 609.3 – 439 – – 64.96 283.45 65.15 657.46 259.72 – 65.63 94.15 143.73 – 97.66 78.76

492.87 664.98 321.69 213.93 222.62 283.41 45.83 307.10 59.39 735.88 220.78 170.42 30.04 101.98 115.02 125.03 140.85 51.14

– 843.62 (4.5 mo) 239.35 (8 mo) 218.29 (4 mo) 140.24 (4 mo) 252.45 (10 mo) – – – – 263.99 (5 mo) – 44.14 (5 mo) – 109.99 (5 mo) 173.03 (4 mo) 111.16 (4 mo) 38.98 (4 mo)

217.2 6 60.3

238.5 6 47.1

221.3 6 63.6

,0.001

,0.001

P-value versus initial volume

395.4 6 69.2

aDesire

for pregnancy. mo 5 months.

Figure 1. Changes in the uterine volume in 18 patients with leiomyomas after 3 months of s.c. administration of the luteinizing hormone-releasing hormone antagonist Cetrorelix (SB-75) in doses of 5 mg twice daily for 48 h followed by 0.8 mg twice daily for 3 months. Case no. 3 did not respond at 3 months, but later uterine volume decreased. Case no. 6 did not respond. Case nos. 1, 2, 14 and 17 (*) showed a reduction in uterine volume in spite of maintaining serum luteinizing hormone within normal limits.

satisfied, showed a mean uterine volume of 212 6 22.1 ml which decreased after therapy to 108.3 6 23.7 ml (48.9% reduction). After the treatment with Cetrorelix a surgical myomectomy was performed in 12 women. No lesions in the endometrial cavity occurred. In three patients it was necessary to perform total hysterectomy. This was due to uterine bleeding at 3 months after treatment (case no. 15), a myoma that was not possible to dissect due to the invasion into the endometrium (case no. 16) and lack of compliance with the treatment protocol (case no. 12). In this case, after 3 months of inconsistent therapy, the administration of the antagonist was stopped and it was necessary to perform total hysterectomy 6 months later. In all other cases, Cetrorelix was administered until the day of the 2030

surgery. Three of the 18 patients had good responses to therapy with Cetrorelix (case no. 9 for 3 months and cases nos. 17 and 18 for 4 months) and it was decided not to perform any surgery, but to follow them by observation. Eleven patients received the first dose of Cetrorelix in the follicular phase (mean cycle day 5.7 6 1.1) and seven during the luteal phase (mean 17.7 6 1.3 cycle days). All patients showed uterine bleeding after 4.6 6 1.0 days of treatment, but its duration in the group which started the therapy in the follicular phase was 8.9 6 1.4 days as compared with 9.4 6 1.9 days for the luteal phase group. There were no apparent differences in the shrinkage of the uterine volume between these two groups. Subsequently, 15 patients became amenorrhoeic during the treatment period. One patient, who missed several injections of Cetrorelix (case no. 3), complained of intermittent vaginal spotting and two patients (case nos. 2 and 14), in whom gonadotrophin concentrations remained within normal limits, had menstrual bleeding after 3 months of therapy. Fourteen patients showed a progressive decrease in serum concentrations of LH, FSH and oestradiol following the first dose of Cetrorelix, maximal inhibition being seen at 6–9 h after the administration. Subsequently, hormonal concentrations declined further and remained at subnormal concentrations throughout the period of LH-RH antagonist administration. Figure 2 shows mean LH and FSH concentrations and Figure 3 mean serum oestradiol of 14 patients. Serum concentrations of LH and oestradiol in 14 patients before and after Cetrorelix are presented in Table II. In four patients (case nos. 1, 2, 14 and 17), the serum gonadotrophins and oestradiol concentrations did not show a clear fall after Cetrorelix and remained within normal limits or were only slightly suppressed during the treatment (Figures 4 and 5). Irrespective of the lack


of a clear pituitary and ovarian hormonal suppression, those four patients still showed a significant decrease in the uterine volume by ultrasonography (Table I). Before Cetrorelix administration, 14 patients presented with low haemoglobin concentrations and haematocrit values due to abnormal vaginal bleeding (four patients with menometrorrhagia and 10 with menorrhagia). The haemograms were

Figure 2. Mean serum luteinizing hormone and follicle stimulating hormone concentrations on the day before and during s.c. administration of 5 mg of Cetrorelix every 12 h on days 1 and 2, followed by 0.8 mg twice daily for 3 months in 14 patients with uterine leiomyomas. LH-RH 5 luteinizing hormone-releasing hormone.

Figure 3. Mean serum oestradiol concentrations on the day before and during administration of 5 mg of Cetrorelix every 12 h on days 1 and 2, followed by 0.8 mg twice daily for 3 months in 14 patients with uterine leiomyomas. LH-RH 5 luteinizing hormonereleasing hormone.

normal in four patients. After 3 months of treatment with Cetrorelix, haemoglobin and haematocrit values were normalized in 12 of 14 patients with anaemia. No significant adverse effects or allergic reactions were seen. The main side-effects were caused by oestrogen deprivation, most patients reporting hot flushes. Some increases in appetite and decreases in libido were also seen. These side-effects disappeared 2 weeks after discontinuation of therapy. The 15 patients, in whom the uteri were not surgically removed, have been followed for up to 25 months (2–25 months). Two patients became pregnant. One patient (case no. 7), 31 years old, who had only one child 4 years earlier, showed a reduction in the uterine volume from 297.8 to 45.8 ml after 3 months of treatment with Cetrorelix. A myomectomy was performed and a month later the menstrual cycle returned and she became pregnant the following month. This patient had a normal gestation and gave birth to a healthy child by Caesarean section. The other patient (case no. 9), 32 years old, was treated for 3 months with a reduction in the uterine volume from 141.09 to 55.39 ml. Because of a good response, she was maintained only under observation. One month later, the menstrual cycle returned and she became pregnant for the first time the following month. A control uterine ultrasound was performed on 15 patients 6 weeks after myomectomy or observation and was repeated 6–9 months later. Only two patients, case no. 5 subjected to myomectomy and case no. 18 followed by observation, showed an increase in the uterine volume at 14 and 21 months after therapy, respectively. Case no. 18 showed a uterine volume of 99.41 ml by ultrasound at 6 weeks after therapy. After 1 year the volume was 109.5 ml and the last ultrasound showed 176.57 ml. In other patients, the volume of the uterus did not increase and they maintained normal menstrual cycles. Table III shows the individual changes in the uterine volume and menstrual cycles in the 13 patients who have been observed for .3 months after the discontinuation of therapy with Cetrorelix.

Discussion Uterine leiomyomas (fibromas) constitute a frequent indication for hysterectomy during the reproductive years. In 1990 ~590 000 hysterectomies were performed in the USA at an

Table II. Inhibition of serum luteinizing hormone (LH) and oestradiol in 14 patients with uterine leiomyomas during the administration of the luteinizing hormone-releasing hormone antagonist Cetrorelix (SB-75) Basal B

3h 6h 9h

Day 1

Day 3

Day 5

Day 14

1 month

2 months

3 months

B

B

B

B

B

B

B

3h 6h 9h

3h 6h 9h

3h 6h 9h

6h

6h

6h

6h

LH (IU/l) Mean SEM

4.82 5.36 4.86 5.30 1.20 1.13 1.34 1.24

6.56 2.56 2.04 2.02 2.87 0.83 0.49 0.51

1.28 1.28 1.09 1.24 1.93 0.87 0.79 0.82

1.06 0.79 0.77 1.35 0.45 0.34 0.32 0.82

0.69 0.58 0.31 0.22

0.43 0.38 0.14 0.14

1.0 0.91 0.37 0.41

1.97 1.65 0.61 0.53

Oestradiol (pg/ml) Mean 82.0 74.9 82.6 108 SEM 21.5 21.3 26.1 26.3

71.1 59.6 60.6 56.2 42.0 31.8 34.5 31.0

29.0 27.7 26.6 25.2 18.5 17.2 19.5 19.2

8.96 9.87 5.30 9.50 4.77 4.28 3.31 3.98

5.75 4.91 1.27 2.59

12.2 6.41 5.62 3.56

4.64 0.26 3.62 0.15

10.8 6.15 6.35 2.17

B 5 basal.

2031


Figure 4. Mean serum luteinizing hormone (LH) concentrations in four patients with uterine leiomyomas (case nos. 1, 2, 14 and 17). In these patients LH concentrations remained within normal limits during the administration of Cetrorelix for 3 months, but a decrease in uterine volume was produced. LH-RH 5 luteinizing hormone-releasing hormone.

Figure 5. Serum oestradiol concentrations in four patients with uterine leiomyomas (cases nos. 1, 2, 14 and 17). In these patients oestradiol concentrations remained within normal limits during the administration of Cetrorelix for 3 months, but a decrease in uterine volume was produced. LH-RH 5 luteinizing hormone-releasing hormone.

estimated expense of five billion dollars (Graves, 1992; Wilcox et al., 1994). Two-thirds of all hysterectomies were performed for non-cancerous conditions such as uterine leiomyoma or endometriosis (Wilcox et al., 1994). Leiomyomas are considered to be sex steroid dependent since they grow during the reproductive years, are rarely seen before puberty and their progression stops after menopause (Buttram and Reiter, 1981; Cramer et al., 1985; Tamaya et al., 1985; Neves-e-Castro and Corrreia, 1987; Santoro et al., 1996). 2032

Administration of LH-RH analogues produces a condition of oestrogen deprivation (Schally 1989; Schally et al., 1993). Therapy with LH-RH agonists has provided a useful medical management in many patients with uterine leiomyomas, especially in young women with low fertility who still desired to become pregnant (Filicori et al., 1983; Healy et al., 1984; Coddington et al., 1986; Lumsden et al., 1987; Neves-eCastro and Correia, 1987; Perl et al., 1987; van Leusden and Dogterom, 1988; George et al., 1989; Letterie et al., 1989;


Table III. Individual follow-up in 13 patients in whom the uterus was not surgically removed Case no.

6 weeks postmyomectomy

Follow-up (months)

Last uterine volume (ml)

Menstrual cycle Lengthsa

Pattern Normal Normal Normal Normal Menometrorrhagia Normal Normal Normal Normal Normal – Normal Menometrorrhagia

1 2 3 4 5 6 7 11 13 14 9b 17b 18b

128.18 – 112.81 166.53 102.18 121.06 Pregnant 125.4 82.04 61.26 42.16a 110.0 99.41

9 9 19 3 14 19 16 10 17 13 5 25 21

127.45 118.32 140.07 166.53 170.68 98.24 – 99.27 89.49 55.77 Pregnant 100.65 176.57

2834 2533 3233 2833 2036 3034 2833 2833 2533 2734 2933 2833 2038

Mean

104.63

13.84

122.09

26.6933.8

SEM

9.77

1.72

11.03

aExpressed as mean days per cycle3no. of cycles. bThese patients were not subjected to myomectomy.

Schally, 1989; Friedman et al., 1989, 1990, 1991; Schally et al., 1993; Lemay et al., 1994; Ayala et al., 1995). Uterine leiomyomas have been demonstrated to have receptors for oestrogen and progesterone (Rein et al., 1990), as well as specific binding sites for gonadotrophin-releasing hormone (Wiznitzer et al., 1988). Rein et al. (1990) found a significant increase in oestrogen and progesterone receptor content of fibroid tissue obtained following 4 months of administration of LH-RH agonist leuprolide as compared with the placebo group. This finding could explain rapid regrowth of myomas after cessation of therapy with LH-RH agonists (Rein et al., 1990). The shrinkage of myomas is normally only achieved after 4–8 weeks of therapy with LH-RH agonists (Healy et al., 1984; Coddington et al., 1986; Lumsden et al., 1987; Nevese-Castro and Correia, 1987; Letterie et al., 1989). LH-RH antagonists cause an immediate inhibition of the pituitary– gonadal axis and produce rapid therapeutic effects (Bajusz et al., 1988; Behre et al., 1992; Schally, 1989; Klingmuller et al., 1993; Schally et al., 1993; Gonzalez-Barcena et al., 1994a,b, 1995; Reissmann et al., 1994). Recently, Kettel et al. (1993) showed a significant regression of leiomyomas after 1 month of therapy with Nal-Glu LH-RH antagonist. Our results also demonstrate the efficacy of pre-operative administration of the antagonistic analogue Cetrorelix in women with myomas scheduled to undergo surgical hysterectomy. Chronic administration of Cetrorelix produces a reduction in the size of the uterus and hysterectomies planned in some patients could be avoided. Clinical improvement in patients with leiomyomas and the uterine shrinkage produced by Cetrorelix treatment is likely to be due to an immediate blockade of the pituitary–ovarian axis and a significant reduction in uterine size could be achieved in 13 patients even after the first month of therapy. In three other patients, uterine volume reduction was seen after 3 months of therapy. In one patient, a delayed uterine shrinkage occurred after 8 months of treatment and one patient

0.15

The values are at 6 weeks after Cetrorelix therapy.

did not respond, probably due to lack of compliance. Before the therapy with Cetrorelix, our patients were considered candidates for a total hysterectomy, but after treatment with this antagonist a myomectomy could be performed in 12 patients and hysterectomy was necessary only in three patients. Of the three patients who did not undergo surgical intervention, one became pregnant 2 months later, in the other patient the uterine volume remained unchanged for the duration of the follow-up of 2 years, and the third patient showed an increase at 21 months after cessation of therapy. It is possible the LHRH antagonists may turn out to be superior to the agonists for treatment of leiomyomas (Kettel et al., 1993). However, additional comparative studies are necessary to demonstrate that the antagonists produce therapeutic effects more rapidly than agonists and that these effects are sustained. The oestrogen receptor content and the regrowth of myomas after therapy with antagonists will likewise have to be investigated. In the patients who did not undergo hysterectomy, normal menstrual cycles were restored within 1 month of the cessation of therapy. A complete recovery of the pituitary–ovarian function after withdrawal of Cetrorelix may be beneficial to those women with fibroids who have not yet completed their families. This approach provides the opportunity to combine the reduced risk of surgery with a possibility of pregnancy. The principal mechanisms by which LH-RH antagonists like Cetrorelix reduce the uterine volume appear to be due to the desensitization of gonadotrophs, competitive LH-RH receptor occupancy and a possible decrease in the concentrations of receptors for LH-RH in the pituitary (Pinski et al., 1993, 1996; Schally et al., 1995; Halmos et al., 1996), with a consequent decline in the secretion of ovarian oestrogen. Nevertheless, some direct effect must be also considered (Schally et al., 1993). High affinity binding sites for LH-RH have been detected in endometriotic tissue and in a high proportion of gynaecological tumours such as uterine myomas, endometrial carcinomas, epithelial ovarian cancers and stromal 2033


tumours of the ovary (Wiznitzer et al., 1988; Schally et al., 1993; Emons and Schally, 1994; Imai et al., 1994a;b). Experimental studies have shown that Cetrorelix inhibits growth of oestrogen-sensitive MXT mammary cancers in mice, Dunning R-3327H prostate cancer in rats and PC-82 human prostate carcinomas and human epithelial ovarian cancers in nude mice (Redding et al., 1982; Schally, 1989; Szende et al., 1990; Yano et al., 1994). These effects are mostly due to the suppression of pituitary–gonadal axis. However, it has also been documented that Cetrorelix can inhibit in-vitro proliferation of human ovarian and endometrial cancer lines (Emons and Schally, 1994; Yano et al., 1994). Leiomyomas are also sensitive to epidermal growth factor and insulin-like growth factor-I (Rein et al., 1990) and these growth factors or their receptors appear to be affected by Cetrorelix administration (Szende et al., 1990; Schally et al., 1993; Yano et al., 1994). This might explain the shrinkage in uterine volumes in those patients who showed only a slight suppression is oestrogen concentrations. Clinical studies have demonstrated that Cetrorelix can inhibit the secretion of gonadotrophins and sex steroids in men and women in doses lower than those used with other LH-RH antagonists, such as Detirelix, Ganirelix, Nal-Glu, and Antide (Schally, 1989; Behre et al., 1992; Klingmuller et al., 1993; Schally et al., 1993; Gonzalez-Barcena et al., 1994a). A somewhat smaller suppression of FSH than that of LH was also previously observed after treatment with Cetrorelix in normal men (Behre et al., 1992; Klingmuller et al., 1993; Gonzalez-Barcena et al., 1994a), some patients with benign prostatic hyperplasia (BPH) (Gonzalez-Barcena et al., 1994b), women with gonadal dysgenesis and post-menopausal women (Gonzalez-Barcena et al., 1994a). The suppression of FSH is partial and appears to depend on doses of Cetrorelix. Cetrorelix causes no or only minimal local side-effects in contrast to other LH-RH analogues such as Nal-Glu antagonist (Behre et al., 1992; Klingmuller et al., 1993; Schally et al., 1993). Cetrorelix has been successfully used in IVF–embryo transfer programmes (Olivennes et al., 1994; Reissmann et al., 1995) and for treatment of BPH and prostate cancer (GonzalezBarcena et al., 1994b, 1995). Recently, depot preparation of Cetrorelix have been reported, which induces an immediate clinical response and which may permit periodic administration (Reissmann et al., 1996). Our study in women with uterine leiomyomas suggests that the pre-operative treatment with Cetrorelix may facilitate myomectomy avoiding a hysterectomy, especially in young patients who still desire to become pregnant. In addition, a decrease in intra- and post-operative morbidity, the duration of hospital stay and the recovery period, and a reduction in the overall cost of treatment may be achieved.

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