One year comparison between two add-back therapies in patients treated with a GnRH agonist for symptomatic endometriosis: a randomized double-blind trial

H. Fernandez1,7, C. Lucas2, B. Hédon3, J.L. Meyer4, J.M. Mayenga5 and C. Roux6

1 Service de Gynécologie-Obstétrique, Hôpital Antoine Béclère, AP-HP, 92141 Clamart, 2 Laboratoires Takeda, 92816 Puteaux, 3 Service de Gynécologie-Obstétrique, Hôpital Universitaire Arnaud de Villeneuve, 34295 Montpellier, 4 Beaumont Clinic, 63110 Beaumont, 5 Service de Gynécologie-Obstétrique, Hôpital Jean Rostand, 92311 Sèvres and 6 Service de Rhumatologie, Hôpital Cochin, Université René-Descartes, 75014 Paris, France

7 To whom correspondence should be addressed. e-mail: herve.fernandez{at}abc.ap-hop-paris.fr


    Abstract
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 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
BACKGROUND: It has been proposed that hormonal supplementation during prolonged GnRH agonist therapy prevents hypoestrogenic side effects, including bone loss. The optimal combination for long-term treatments with safe metabolic profile remains questionable. A norprogesterone derivative, promegestone, was assessed for the first time in a double-blind trial. METHODS: Seventy-eight patients with endometriosis with rAFS (Revised American Society for Reproductive Medicine) scores of III–IV were randomly assigned to monthly leuprorelin 3.75 mg (1 year) which, after the third injection was used in combination with promegestone 0.5 mg (P) plus either estradiol placebo (PL) or estradiol 2 mg (E) per day. Bone mineral density (BMD) was determined at baseline, 6 and 12 months, and biological and clinical quarterly assessments were performed. Analysis was by the intention to treat method. RESULTS: At month 12, BMD changes from baseline were –6.1 ± 3.7 and –4.9 ± 4.0% in the PL-P group, at the spine and hip, respectively. This bone loss was prevented in the E-P group: –1.9 ± 3.1 and –1.4 ± 2.3%, respectively (P < 0.0001 inter-group comparisons). The BMD decrease in the E-P group was explained by the changes occurring during the first 6 months of treatment. There was no deleterious change in lipid parameters. Clinical improvement was observed without an inter-group difference. CONCLUSIONS: Estradiol 2 mg and promegestone 0.5 mg per day is an effective and safe add-back therapy, which can be proposed for prolonged leuprorelin treatment over 6 months in severe endometriosis.

Key words: add-back therapy/bone mineral density/endometriosis/GnRH agonists/leuprorelin


    Introduction
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
GnRH agonists desensitize GnRH receptors of the pituitary gland when there is continued exposure, which causes an initial stimulation of the pituitary–ovarian axis, followed by a reduction in circulating serum gonadotrophin concentration and inhibition of ovarian function. They have been shown to be effective in the treatment of several sex hormone-dependent conditions, especially endometriosis, leading to atrophy of both the endometrium and the endometriotic tissues (Shaw, 1992Go).

However, adverse effects reported by women receiving GnRH agonist treatment are those of secondary hypogonadism (hot flushes, sweating, vaginal dryness, etc.) (Scharla et al., 1990Go; Surrey and Judd, 1992Go; Friedman et al., 1993aGo; Leather et al., 1993Go; Pierce et al., 2000Go). Furthermore, this treatment induces a dramatic decrease in bone mineral density (BMD), higher than in the early months of natural menopause, reaching 4–5% at the lumbar spine in 6 months (Roux et al., 1995Go; Moghissi et al., 1998Go; Franke et al., 2000Go). This bone loss has been found to be reversible in most studies, but the point is debated (Surrey et al., 1990Go; Paoletti et al., 1996Go; Pierce et al., 2000Go). These adverse effects limit the duration of treatment in diseases that are chronic or recurrent by nature. There is thus a clinical need to counter bone loss without impairing the induced hypoestrogenism and the efficacy of the treatment (Pickergill, 1998Go; Surrey, 1999Go). We have shown previously that calcitonin, an antiosteoclastic drug, is unable to prevent agonist-induced bone loss (Roux et al., 1995Go; Borderie et al., 1998Go). Add-back hormone replacement therapy, in which various steroid agents are combined with GnRH agonist therapy, has been recommended as a means of maintaining a therapeutic response and preventing potential adverse effects of GnRH agonist treatment in patients with myomas (Friedman et al., 1993bGo; Lindsay et al., 1996Go) and endometriosis (Surrey and Judd, 1992Go; Howell et al., 1995Go; Kiiholma et al., 1995Go; Makarainen et al., 1996Go; Taskin et al., 1997Go; Hornstein et al., 1998Go; Surrey, 1999Go; Franke et al., 2000Go; Pierce et al., 2000Go). The bone effect is thought to be related to the estrogen component, providing that the dose is correct. However, some progestins may have their own positive effect on bone (Riis et al., 1990Go), but with questionable effects on lipids.

We conducted this prospective double-blind 1 year study in order to compare the effects of estradiol plus promegestone versus promegestone alone in preventing bone loss and in reducing the vasomotor symptoms without compromising the lipid parameters, and the efficacy of the treatment in women treated with a GnRH agonist for severe endometriosis.


    Materials and methods
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 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Patients
Patients suffering from symptomatic endometriosis were recruited from 22 French gynaecological centres for the study. Endometriosis was scored according to the revised American Fertility Society (rAFS) classification (Revised American Society for Reproductive Medicine, 1997Go) at the time of a laparoscopy performed before initiation of treatment, and a pathological confirmation was required. Patients eligible for study inclusion were pre-menopausal women with rAFS stage III–IV endometriosis, over 18 years of age with regular menstrual cycles. Patients taking drugs known to affect bone metabolism, and patients with evidence of a major developing associated disease (such as renal or hepatic failure, severe psychiatric disorder, malignancy and cardiac disease), or wishing to become pregnant were excluded. Patients with collagen disease, porphyria, obesity, previous thromboembolism, confirmed diabetes, hyperlipidaemia or with otosclerosis which developed during a pregnancy could not participate, as well as any patient with hormone-dependent neoplasia. Patients should have stopped any hormonal treatment >1 month prior to study entry.

Study design and treatments
The study was a double-blind, randomized, placebo controlled trial of 1 year duration. Written approval for the study was obtained from the Ethical Review Board of the University Paris-Cochin. All patients gave signed informed consent before inclusion.

All patients were treated with long-acting leuprorelin (Takeda, Puteaux, France), given as one s.c. injection (3.75 mg) at monthly intervals for 12 months. Therapy was started during menstruation.

Patients were randomly assigned to one of two treatment groups: promegestone 0.5 mg and placebo (group I), or estradiol 2 mg/day and promegestone 0.5 mg (group II), taken daily orally. This add-back therapy was begun at week 9 after the first administration of GnRH agonist (concomitantly with the third injection) in order to limit any possible hormonal interactions before patients could benefit from the atrophy of the endometriotic lesions and in order to obtain a quick sedation of pelvic pain. The patients were randomized by centre according to permuted blocks of treatment (block size: 4). An external company in charge of treatment packaging and treatment masking generated the allocated sequence list that was kept centrally for blinding.

Clinical assessment
A clinical assessment was made at entry visit, then at the 3, 6, 9 and 12 month visits. This included clinical examination with assessment of pelvic pain, dysmenorrhoea, dyspareunia, pelvic tenderness and duration, rated on a 0–3 scale (none, mild, moderate and severe pain) according to the Biberoglu and Behrman grading scale (Biberoglu and Behrman, 1981Go). A total score was calculated, based on these five symptoms or signs. Specific detailed information was also collected during each visit for menorrhagia, climateric symptoms and headaches. The latter two subjective side effects were graded using a visual analogue scale (0–100 mm). Adverse events and concomitant therapeutics were recorded.

Bone mineral density measurements
BMD (g/m2) was measured at baseline and after 6 and 12 months by dual-energy X ray absorptiometry (DEXA). Because of the multicentre design of the study, 16 separate apparatuses were used (14 Hologic, two Lunar). All the scans were sent to a central facility where a standardized analysis was performed, by an investigator blinded to the treatments and symptoms of patients. At the lumbar spine, the second, third and fourth vertebrae were measured (antero-posterior view). At the upper extremity of the left femur, the neck, great trochanteric and total areas were considered. All the examinations were performed according to the manufacturers’ recommendations. A technical manual was provided to all centres at baseline, and each centre was requested to send the quality control of the device on a monthly basis, i.e. the result of the measurement (at least three times a week) of a spine phantom provided by the manufacturer. In the central facility, the results were checked to avoid any drift.

Lumbar T-scores (i.e. the number of SDs relative to young normal sex-matched subjects) were calculated at baseline. In our laboratory, the short-term precision of DEXA measurements in young subjects is 1% on average at the lumbar spine.

Laboratory assessment
Laboratory assessment was made on an out-patient basis and samples were assayed at a central reference laboratory.

Biochemical markers of bone remodelling were assessed at entry and then every 3 months. Blood and urine samples were taken after a 12 h overnight fast, and tobacco abstinence was advised. Pyridinoline/creatinine ratio (as a specific marker of bone resorption) (normal range 2–6 nmol/nmol), and serum osteocalcin (normal range 10–32 µg/l) (as a marker of bone formation and remodelling) were measured using enzyme-linked immunosorbent assay (ELISA) and radioimmunoassay (RIA) methods, respectively.

Serum estradiol (RIA after extraction), progesterone (RIA), LH and FSH (microparticle enzyme immunoassay) concentrations were measured at entry visit, on day 3 of the cycle, then monthly for 6 months, and at 9 and 12 months (before GnRH agonist injection). The upper limits of the intra and inter-assay coefficients of variation were, respectively, 9.7 and 10.2%, 6.4 and 9.1%, 4.5 and 5.2%, and 4.3 and 6.1%.

Blood lipids and glucose were measured using standard methods.

Samples for these determinations were stored at –20°C. Samples from each woman were analysed in the same assay to eliminate inter-assay variation.

Statistical analysis
The two main evaluation criteria were the percentage changes between baseline and month 12 in BMD at the lumbar spine (according to the main reader, blind to treatments and clinical/biological assessments) for assessing bone loss, and pelvic pain score for clinical efficacy. Secondary efficacy criteria were the changes at the femur and the biochemical markers of bone remodelling, and other clinical signs and symptoms, safety and tolerability.

Results are expressed as the mean ± SD unless otherwise indicated. The statistical analysis was performed on an intention to treat (ITT) basis. Treatment groups were compared using the {chi}2 test, Fisher’s method and Student’s t-test. The paired difference t-test was used to compare within-group differences when the difference was from a normal distribution, and the Wilcoxon matched pairs signed rank test was used otherwise. A P-value <0.05 was considered significant. At the time of study planning, no precise calculation of population sample size could be performed on the main criteria (relative variation of bone density in a period of 12 months and pelvic pain score).


    Results
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 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Patients and study course
Seventy-eight patients were randomized in this study from 1997 to 2000 and included in the ITT analysis for both safety and clinical assessment. We did not calculate the sample size for this study because of the absence of data at the beginning of the study. In spite of the patient numbers included and without knowing the number of potential premature withdrawals and protocol deviations, enrolment of patients was stopped after 3 years.

One patient in each group was excluded from the ITT analysis for BMD evaluation because a technical problem precluded the analysis. Fourteen patients withdrew prematurely from the study. After the exclusion of 10 patients with major protocol deviations, i.e. inclusion criteria (mainly lack of histological proof of endometriosis), treatment compliance, protocol schedule and code break in two cases, the results obtained from the per protocol analysis did not differ from the ITT. The two groups were similar with respect to baseline characteristics (Table I). For ITT, data on the BMD evaluation criterion (changes between baseline and month 12) were available in 59 patients, and pelvic pain score rating was available in 71 and 61 patients at month 6 and 12, respectively.


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Table I. Characteristics of patients at baseline
 
Efficacy assessment
BMD. At the entry visit, lumbar spine BMD was within the normal range: T score was –0.42 ± 0.89 (n = 59) and 0.51 ± 0.81 (n = 15) on the Hologic and Lunar devices, respectively. There was no baseline difference in BMD between the two treatment groups.

The results of BMD changes are given in Figure 1. There was a statistically significant difference in BMD change between the two groups at all sites measured between baseline and month 12. As compared with baseline, the decrease was statistically significant in both groups but less important in the estradiol-treated group: –6.1 ± 3.7 and –1.9 ± 3.1% (P < 0.0001) for the placebo and estradiol-treated groups, respectively, at the lumbar spine. This decrease was –4.9 ± 4.0 and –1.4 ± 2.3%, respectively, at the total hip (P < 0.0001) and –5.0 ± 4.0 and –2.3 ± 3.3% at the femoral neck (P = 0.0064). In the placebo-treated group, the lumbar spine BMD change was –3.9 ± 2.9% (P < 0.0001) during the first 6 months and –2.2 ± 2.7% (P < 0.0001) during the following 6 month period. In contrast, the decrease observed in the estradiol-treated group at month 12 compared with baseline was mainly related to changes which occurred within the first 6 months of the study (–1.5 ± 2.4%, P = 0.0026), as during the second period the change of –0.3 ± 2.7% was not statistically significant (P = 0.651). Based on the precision method, a change >2.8% at 1 year was considered as significant at the individual level. Such a decrease was observed at the lumbar spine in 90.0% of patients for the placebo group and 34.5% for the estradiol group (P < 10–4). These proportions were 60 and 19.4% at the total hip (P = 0.0012).



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Figure 1. Changes in bone mineral density at the lumbar spine and total femur: baseline, 6th month and 12th month of leuprorelin 3.75 mg treatment combined with either estradiol and promegestone (group II) or placebo and promegestone (group I).

 
Biochemical assessment of bone metabolism. The changes in the biochemical estimates of bone resorption and formation were commensurate with an estrogenic deprivation in the placebo group, and these changes were not observed in the estradiol group. The pyridinoline/creatine ratio was different between the two groups at 6 (P = 0.008) and 12 months (P = 0.02), and osteocalcin was different at 12 months (P < 0.0001).

Clinical response. No significant statistical difference was noticed either in pelvic pain intensity scoring (the mean score at baseline of 2.08 ± 0.81 in the placebo group and 2.08 ± 0.84 in the estradiol group decreased to 0.28 ± 0.53 and 0.50 ± 0.84 at 12 months, respectively; the final median scores were 0 in both groups) or in total signs scoring according to the Biberoglu and Behrman rating scale; the mean decrease from baseline was 77 and 89%, respectively, after 1 year.

The proportions of patients who observed vaginal bleeding or spotting during the study were not statistically significant different between the treatment groups: 85.3% in the placebo group and 87.9% in the estradiol group.

Endocrinological effects. As expected, we observed a significant decrease in gonadotrophin, (in particular serum LH) and serum estradiol after initiation of treatment with the GnRH agonist. Low concentrations were maintained throughout the study period at values close to those observed at menopause in the two groups. Nevertheless, as expected, the mean serum estradiol levels were constantly significantly higher at each time point in the treated group compared with those of the placebo group. FSH levels also remained significantly lower in the group receiving the estrogen–progestin combination, due to probable negative feedback of exogenous estradiol. The LH and progesterone levels were comparable in the two groups.

Safety assessment
Biological safety. The results of the serum lipid and glucose analysis at baseline and during the study are summarized in Table II. No significant change was observed in lipid and glucose metabolism in both groups; only small changes in serum glucose and the low-density lipoprotein (LDL)/high-density lipoprotein (HDL) ratio were statistically significant at 12 months but without an inter-group statistical difference.


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Table II. Changes at 12 months (from baseline) in serum estradiol, lipids and glucose
 

Adverse events. The incidence of adverse events was comparable between groups (97.4% of women in each group with a mean number of 9.6 and 8.3 adverse events per patient in the placebo and estradiol groups, respectively). No adverse event occurred more frequently in one of the treatment groups. The main reported side effects were hot flushes and headaches, the intensity of which, when evaluated on a visual analogue scale, did not reveal any significant difference between the two groups (Figure 2). Fourteen events (seven in each group) resulted in discontinuation of the study for 10 patients: one case of depression, two cases of hot flushes, two of weight increase, two of vaginal dryness, one of impairment of libido, one of increase of appetite, one of a local reaction at the injection site, one of metrorragia, one of asthenia, and two trombophlebitis events which both occurred in the promegestone group in patients who had a previous history of such events.



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Figure 2. Evolution of the intensity of hot flushes and headache rating: baseline, months 3, 6 and 12 (visual analogue scale) in patients treated with leuprorelin 3.75 mg treatment combined with either estradiol and promegestone (group II) or placebo and promegestone (group I).

 
Eight serious adverse events were reported in six patients (three in each group): in the estradiol group, one case of sciatalgia with a suicide attempt, one case of asthenia, and two psychotic depression events in the same patient; and in the other group, one case each of dizziness, recurrence of endometriotic cyst and thrombophlebitis. Only one, the latter, resulted in discontinuation of the study, in the placebo group. The investigators assessed that the three events reported in the estradiol group were not related to the study treatment.


    Discussion
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 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Our data suggest that a 1 year add-back therapy with 2 mg of estradiol and 0.5 mg of promegestone administered daily orally, in combination with 3.75 mg of leuprorelin injected once monthly, is effective in the prevention of agonist-induced bone loss. Moreover, our study demonstrates this efficacy at both the lumbar spine and the femur.

Even if a power calculation was not performed at the beginning of the study, the sample size seems to be sufficient to support the findings. As a matter of fact, intrinsic variability related to the techniques for bone density measurements leads to a 2.8% margin. By analogy to what is accepted on an individual level, we can estimate that any difference >2.8% is clinically significant. On this basis, in a two-sided testing, with a type 1 error rate of 5% and a 95% power, 24 subjects per arm would have been required in order to demonstrate that the treatment including estradiol leads to a reduction of bone density compared with the other treatment arm. As a 4.2% difference between groups was found with 59 patients, the clinical relevance of the significant statistical findings on the main criteria was ensured. On the other hand, all the various hormonal combinations published in the literature as add-back therapy showed a similar efficacy on clinical improvement, and no difference between groups was expected with regard to pelvic pain. Consequently, the main criterion was not based on clinical findings, but on bone assessment.

Clinical improvement was high in the two groups both for pelvic pain and for all signs and symptoms of endometriosis. Although there was no control group receiving leuprorelin alone, this improvement is similar to that generally observed with the agonist alone (Hornstein et al., 1998Go).

Previous studies have shown that a high proportion of women had symptoms which returned to baseline levels <6 months after a 6 month GnRH agonist treatment course, indicating the need for long-term, but safe, treatment (Surrey and Hornstein, 2002Go). As a matter of fact, pelvic pain in women with severe endometriosis is often resistant to other medical therapies, in particular anti-gonadotrophic progestins and repeated surgery are not always desirable or adequate. Bone loss is the main restriction in duration of use of GnRH agonists. Proposals for partial replacement therapy with progestins or estrogen–progestins have thus been investigated in several controlled or non-controlled studies, in association with long-term GnRH agonist treatment (Pierce et al., 2000Go; Surrey and Hornstein, 2002Go).

In the group treated with estradiol, we observed a slight BMD decrease of –1.9% after 12 months; this bone loss is actually explained by the change occurring during the first 6 months, during which patients were treated for only 4 months, as no significant bone change was measured during the last 6 months of the study. Moreover, this change is similar to that observed after 1 year of 5 mg daily norethindrone acetate in women receiving leuprorelin (Hornstein et al., 1998Go). In contrast, in patients treated with 0.5 mg of promegestone alone, we observed a change in BMD similar to the one expected in the absence of add-back therapy (Hornstein et al., 1998Go). Tremolieres et al. (1993Go) evaluated a preventive effect of this 19-norpregnane progestin against bone loss versus placebo for 2 years in post-menopausal women, which justifies the choice of this progestin in this trial. Nevertheless, our results could not confirm any benefit of the combination with promegestone alone as compared with previous published results on a 1 year treatment with leuprorelin. This observation is probably related to the choice of the progestin in our study, considering the favourable results on bone density previously observed with norethindrone. With this last treatment combination, however, a significant increase in LDL cholesterol and triglycerides is observed. When conjugated equine estrogens are used in combination with this progestogen, other deleterious effects including an increase in total cholesterol and decrease in HDL cholesterol are observed (Hornstein et al., 1998Go). Lower doses of norethindrone, although they decreased the side effects of the GnRH agonist, have not demonstrated any effect in the protection of bone mass (Surrey et al., 1990Go).

Considering the lack of promegestone’s effect on bone density, one may question the usefulness of the addition of promegestone for a duration limited to 10 months, and the real risk of endometrial cell proliferation associated with estradiol supplementation alone at a 2 mg daily dose (Pickergill, 1998Go). Furthermore, the study protocol planned initiation of add-back at the beginning of the third month of the GnRH agonist treatment because an immediate impact on bone of the GnRH agonist was not expected: the sharp drop in estradiol at the threshold of menopause is achieved with certainty only 3 or 4 weeks after the first injection is administered. Moreover, we chose to delay the onset of add-back therapy in order to limit the exposure to possible disease recurrence in this selected population with severe endometriosis. Even so, in other series of patients, concomitant starting of add-back therapy was chosen (Gregoriou et al., 1997Go; Freundl et al., 1998Go; Pickergill, 1998Go) and the question remains regarding the optimum time for the initiation of hormone replacement therapy. There is no adequate answer in the literature to determine the best time schedule for starting add-back therapy and there is no difference in BMD whatever the delay chosen.

Benefits in limiting menopausal symptoms could not be evaluated because of the lack of a control arm receiving only leuprorelin, and it seems hazardous objectively to put our results into a perspective comparison with those observed in other series (in which add-back therapy regimens were used or studies without add-back). Indeed, these parameters are highly dependent on the methods used for collecting data and on duration of follow-up. Nevertheless, the overall safety and tolerability profile appeared satisfactory, with few discontinuations of treatment with regard to the duration of the study in young patients.

The adjunction of estradiol and promegestone optimizes the GnRH agonist treatment and authorizes a treatment for >24 weeks with limited side effects, without BMD alteration and without recurrence of endometriosis.


    Acknowledgements
 
The authors wish to express their gratitude to Franck Sevenier, Fovea, for his assistance with statistical analyses and review of the statistical methods. This work was supported by a grant from Laboratoires Takeda, France.

Add-back Study Group: Sandrine Avigdor, Jean-Jacques Baldauf, André Benbassa, Gilles Burlet, Michel Collet, Dominique Dallay, Hervé Dechaud, Philippe Descamps, Erwann Durouchet, Jean-Marc Mayenga, Anne Gompel, Michel Herlicoviez, Philippe Judlin, Jean-Louis Leroy, Patrick Madelenat, Omar Mekouar, Philippe Michaud, Xavier Monrozies, Olivier Parant, Jacques Salvat, Vincent Servajean, Didier Tardif, Yves Thebault, Grégoire Thery, Fabrice Truong Canh, Jean Vialard.


    References
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
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Submitted on April 25, 2003; accepted on March 16, 2004.





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