Volume 154, Issue 1 , Pages 85-89, January 2011
The efficacy and tolerability of short-term low-dose estrogen-only add-back therapy during post-operative GnRH agonist treatment for endometriosis
Article Outline
- Abstract
- 1. Introduction
- 2. Materials and methods
- 3. Results
- 4. Comment
- Acknowledgement
- References
- Copyright
Abstract
Objective
To evaluate the efficacy and tolerability of a low-dose estrogen-only regimen as a short-term add-back therapy during post-operative GnRH agonist (GnRHa) treatment of patients with endometriosis.
Study design
Retrospective cohort study. One hundred seventeen women of reproductive age who were treated with post-operative GnRHa after conservative laparoscopic surgery for endometrioma were eligible for this study. The patients were divided into two groups: group A (n
=56) received tibolone (2.5mg) between 2002 and 2004 and group B (n=61) received estradiol valerate (1mg) between 2005 and 2007 as an add-back therapy for five months, beginning at the time of the second injection of a GnRHa. The incidence of hypoestrogenic symptoms and the degree of pelvic pain according to a verbal rating scale (VRS) scoring system, the incidence and patterns of uterine bleeding during add-back therapy, the endometrial thickness by ultrasonography two months after the last GnRHa treatment, and the serum CA-125 level were evaluated.
Results
The incidence of uterine bleeding, hypoestrogenic symptoms such as hot flashes and sweating, and pelvic pain did not differ significantly between the two treatment groups. However, the endometrium was thicker in group A than group B (p=0.022). In group B, the frequency of uterine bleeding was lower from the second month after starting add-back therapy than in group A, but without statistical significance (at the sixth month, p=0.086).
Conclusion
The low-dose estrogen-only regimen was efficacious and tolerable as a short-term add-back therapy during post-operative GnRHa treatment after surgery for endometriosis.
Keywords: Endometriosis, GnRH agonist, Low-dose estrogen, Add-back therapy
1. Introduction
Endometriosis is the second most common gynecologic disease after fibroids, and affects approximately 10% of women of reproductive age [1], [2]. In the past, endometriosis was treated mainly by surgery. However, as endometriosis recurs based on the severity and duration of the disease (37% in stages I and II, and up to 70% in stages III and IV) [1], [2], [3], [4], many clinicians now consider post-operative medical therapy, including danazol, oral contraceptives, gestrinone, or GnRH agonist (GnRHa).
Among the treatment strategies, the benefits of GnRHa treatment for endometriosis are well-established as an effective strategy for preventing recurrence or managing pain symptoms [5], [6], [7], [8], [9]. However, treatment with GnRHa is generally limited to six months due to concerns about the undesired side effects of prolonged hypoestrogenism, such as climacteric symptoms (hot flashes, sweating, and vaginal dryness) and bone loss [10]. Supplementing GnRHa treatment with a regimen of low-dose combined estrogen/progesterone (E/P) as “add-back” therapy has been suggested to prevent the climacteric symptoms associated with hypoestrogenism and bone loss [11], [12].
Although hypoestrogenic symptoms are relieved by add-back therapy, patient compliance is still a problem due to side effects such as unexpected uterine bleeding. Therefore, our motivation was to find a better regimen than the continuous, combined E/P protocol. However, there is limited information regarding the efficacy and side effects of add-back therapy with other medications.
When we were considering other medications to use, we hypothesized that the hormonal status of premenopausal women receiving GnRH agonist treatment would be similar to that of postmenopausal women. In studies of postmenopausal women, tibolone resulted in a lower incidence of uterine bleeding than a continuous combined E/P regimen, resulting in improved patient compliance [13], [14]. Regarding an E2-only regimen, one study reported that an E2-only regimen resulted in a higher incidence of amenorrhea than a continuous combined E/P regimen during the first three months of treatment, although this result was not statistically significant (88% vs.75%) [15]. In that report, women treated with ethinyl estradiol 5μg had no adverse outcomes, such as endometrial hyperplasia, over a period of six months. Furthermore, in a large, randomized clinical trial, Archer et al. reported that cumulative rates of no bleeding were much higher in the conjugated equine estrogen (CEE) group than the CEE/medroxyprogesterone (MPA) group, especially before six cycles [16]. Although statistical differences between CEE and CEE/MPA were not reported for each cycle, the differences were clear in the first few months.
One study reported the use of an E2-only regimen (oral estradiol 1mg, Estrace®) as a short-term add-back therapy during GnRHa treatment for endometriosis-related pain [17]. These authors did not detect any abnormal endometrial pathology in the study group and stopped the study due to recurrent pain during add-back therapy.
Therefore, we conducted this study to evaluate the efficacy and tolerability of tibolone and a low-dose estrogen-only regimen for short-term add-back therapy during GnRH agonist treatment after surgery for endometriosis.
2. Materials and methods
We reviewed the records of 176 consecutive women who underwent laparoscopic surgery for endometrioma with or without pelvic pain in the Department of Obstetrics and Gynecology of Samsung Medical Center in Seoul, Korea between 2002 and 2007. One hundred twenty-three women received six cycles of post-operative GnRH agonist adjuvant treatment (leuprorelin acetate, Leuplin®, 3.75mg; Takeda, Osaka, Japan) every month. To prevent the side effects of hypoestrogenism, the patients also received daily add-back therapy that began with the second GnRHa injection (Fig. 1). Between 2002 and 2004, 62 patients received add-back therapy with tibolone (Livial®, 2.5mg; Organon, Milan, Italy). Fifty-six patients were eligible for this study, and 6 patients who did not complete the follow-up were excluded (group A). Since 2005, 61 patients received estradiol valerate (Progynova®, 1mg; Shering, Dublin, UK] as add-back therapy and all patients completed the follow-up (group B). We included all consecutive patients except those lost to follow-up, without any specific selection process.
Fig. 1.
Treatment protocol. Immediately after surgery and then at one-monthly intervals, a GnRH agonist was administered (six treatments in total). Add-back therapy was performed for five months beginning one month after surgery. Ultrasound and CA-125 level were evaluated two months after the last GnRH agonist treatment.
To estimate the efficacy and tolerability of the add-back therapy with low-dose estrogen only, we reviewed the hypoestrogenic symptoms, endometriosis symptoms (pelvic pain), and side effects, such as irregular uterine bleeding. Patients were questioned at each visit to assess hypoestrogenic symptoms (hot flashes or sweating during the last month), uterine bleeding, and pelvic pain. Vaginal bleeding patterns were divided into four subtypes as follows: (1) regular menstruation-like bleeding, (2) irregular menstruation-like bleeding, (3) regular vaginal spotting, and (4) irregular vaginal spotting. The degree of pain was measured according to a verbal rating scale (VRS) scoring system that consists of a simple point scale, as follows: 0-none, 1-mild, 2-moderate, and 3-severe.
Ultrasonography was performed two months after the last GnRHa treatment to assess remnant lesions and endometrial thickness. Specialized gynecologic sonographers conducted transvaginal or transrectal ultrasonographs, and all findings were confirmed by two radiologists. The serum CA-125 level was also evaluated at the same time of ultrasonography.
The Institutional Review Board (IRB) of Samsung Medical Center approved this study, and it was determined to be exempt from informed consent requirements because it was a retrospective review of the medical records.
2.1. Statistical analysis
The differences between treatment groups with respect to baseline characteristics were determined using the Mann–Whitney test and a chi-square test. Statistical comparisons of the incidence of symptoms during GnRHa treatment between the two groups were analyzed using a chi-square test and Fisher's exact test, where appropriate. All P-values were two-sided, and a p-value<0.05 was considered to indicate statistical significance.
3. Results
3.1. Demographic profiles
One hundred and seventeen women of reproductive age with endometrioma were enrolled in this study, and received GnRHa therapy combined with tibolone (group A) or low-dose estrogen (estradiol valerate 1mg) only (group B) add-back therapy after pelviscopic surgery. All enrolled patients were operated on mainly due to endometrioma. Complete obliteration of the posterior cul-de-sac with rectal adhesion was noted at surgery in 12 patients in group A and 15 patients in group B. Rectal invasion was not confirmed by biopsy during surgery. Gross evidence of vesical extension was not found during surgery in patients in either of the two groups. There were no significant differences between the two groups in terms of age, age at menarche, parity, body mass index (BMI), regularity of menstrual cycles, and stage of endometriosis (Table 1).
Table 1. Baseline characteristics.
| Tibolone (n=56) | Estradiol valerate (n=61) | |
|---|---|---|
| Age (year) | 28.56±6.63 | 30.31±7.10 |
| BMI | 21.35±1.88 | 20.98±1.79 |
| Parity | ||
| Nullipara | 40 (71.4) | 45 (73.8) |
| Multipara | 16 (28.6) | 16 (26.2) |
| USG during add-back | ||
| Endometrial thicknessa | 5.69±2.42mm | 5.05±3.27mm |
| CA-125 | ||
| Preoperative | 64.33±10.3 | 60.98±13.9 |
| Post GnRH (2 mon) | 17.80±13.35 | 15.67±12.32 |
| Diagnosis | ||
| Unilateral endometrioma | 38 (67.9) | 36 (59.0) |
| Bilateral endometrioma | 18 (32.1) | 25 (41.0) |
| Operation type | ||
| Unilateral cystectomy | 20 (35.7) | 24 (36.9) |
| Bilateral cystectomy | 20 (35.7) | 26 (42.6) |
| USOb | 11 (19.6) | 6 (9.8) |
| Unilateral cystectomy & USO | 5 (8.9) | 5 (8.1) |
| Stage | ||
| III | 42 (75.0) | 45 (73.8) |
| IV | 14 (25.0) | 16 (26.2) |
aDifference in endometrial thickness between the two groups was statistically significant (p |
bUnilateral salpingo-oophorectomy. |
3.2. Incidence of side effects
The hypoestrogenic symptoms induced by GnRHa, such as hot flashes and sweating, and uterine bleeding and pelvic pain, which could be affected by add-back therapy, were evaluated in the two groups. Regarding the incidence of these symptoms during five months of add-back therapy, there was no significant difference between the two add-back treatment groups (Fig. 2).
Fig. 2.
The incidence of symptoms during GnRHa treatment with add-back therapy over five months of add-back treatment. Incidence refers to at least one occurrence of symptoms. The incidence of symptoms was not significantly different between the two add-back treatment groups.
The incidence of hot flashes as hypoestrogenic symptoms was 53.6% and 59.0% in groups A and B, respectively. The incidence was high in the first month after beginning add-back therapy, but markedly decreased two months later in both groups. The incidence each month was not significantly different between the two groups (Fig. 3A). Over five months of add-back treatment period, the incidence of uterine bleeding was not different between groups A and B (44.64% vs. 40.98%, respectively, p=0.25). However, the frequency of uterine bleeding with time was lower in group B than in group A from the second month after beginning add-back therapy, but without statistical significance (at the sixth months, p=0.086) (Fig. 3B).
Fig. 3.
The frequencies of hot flashes and uterine bleeding with time. (A) Hot flashes. (B) Uterine bleeding. Patients received daily add-back therapy beginning at the same time as the second GnRHa injection (second month). The frequency of hot flashes was high in the first month after the initiation of add-back therapy, but decreased markedly in the second month in both groups. The incidence of hot flashes each month was not significantly different between the two groups. The incidence of uterine bleeding decreased with time and was less common in group B than group A patients from the second month after the start of add-back therapy; however, this difference was not statistically significant.
We divided uterine bleeding into four subtypes and the most common pattern of uterine bleeding was irregular vaginal spotting in both groups (66.7% vs. 80.0%, respectively) (Table 2).
Table 2. The distribution of uterine bleeding in two treatment groups.
| Tibolone n (%) | Estradiol valerate n (%) | |
|---|---|---|
| Irregular vaginal spotting | 26 (74.3) | 20 (80.0) |
| Regular vaginal spotting | 4 (11.4) | 2 (8.0) |
| Irregular menstruation-like bleeding | 3 (8.6) | 3 (12.0) |
| Regular menstruation-like bleeding | 2 (5.7) | 0 (0) |
| Total | 35 (100) | 25 (100) |
The pain intensity was measured according to the verbal rating scale (VRS) scoring system before surgery. In group A, 24 patients had mild pain, while 13 had moderate pain and four had severe pain. In group B, 29 patients had mild pain, 12 had moderate pain, and six had severe pain. After the surgery, six women had a mild pelvic pain in group A (10.6%) and five women had mild pain in group B (8.2%) (Fig. 2).
3.3. Ultrasonographic evaluation after completion of GnRHa
We evaluated the endometrial thickness and evidence of residual lesions by ultrasonography two months after the last GnRHa treatment. The endometrium was thicker in group A (median value 5.35mm; range 2.0–17.0mm) than group B (4.3mm; range 1.0–19.0mm; p=0.022). Heterogeneous echogenic ovarian cysts were noted in three patients (group A, two patients; group B, one patient). The clinical impression was benign and resolved over a six-month period.
In addition, the nine patients with abnormal CA-125 values (>35.5) after the completion of GnRHa treatment did not show any clinical or radiologic evidence of disease (Table 1).
4. Comment
GnRH agonists are widely used for the treatment of endometriosis because of their effectiveness in improving endometriosis-related symptoms and suppressing disease recurrence [18], [19]. Treatment with GnRH agonists is generally limited to six months and requires add-back therapy due to GnRH agonist-induced hypoestrogenism [20]. Add-back hormone replacement therapy, in which various agents are combined with GnRH agonist treatment, has been recommended as a means of maintaining therapeutic effects while ameliorating the potential adverse effects of GnRH agonist treatment.
The rationale for the use of add-back hormone replacement therapy can be explained by the estrogen threshold hypothesis [21], which states that low levels of circulating estradiol levels are associated with regression of estrogen-sensitive tissues (e.g., endometriotic implants), and that adding back small amounts of estrogen will increase circulating levels sufficiently to maintain the integrity of some tissues, such as bone, with relief of vasomotor symptoms, while causing other tissues (e.g., endometriotic lesions) to remain in a state of regression.
To find alternative regimens of add-back therapy with fewer side effects, we evaluated the regimens of tibolone and low-dose estrogen only. While some studies in postmenopausal women have raised concerns about endometrial hyperplasia in women treated with estrogen only, we felt that several studies supported the safety of this treatment for short-term use. It was reported that no adverse event was observed within six months when 5μg ethinyl estradiol (EE2) was administered. Endometrial hyperplasia was found after 12 months in one out of 94 patients in the 5μg EE2 group [15]. In 2003, Portman et al. reported only one case of endometrial hyperplasia out of 114 at month 12 in the 5μg EE2 group, an incidence similar to that observed in the placebo group (1/114 vs. 1/115) [22]. They did not report any case of endometrial pathology before month 12.
Tibolone is a synthetic steroid with estrogenic, progestogenic, and androgenic activities [23]. It has been shown that the addition of tibolone to GnRH agonist treatment reduces bone loss and vasomotor symptoms, without reducing the therapeutic effect of the GnRH agonist in endometriosis patients [24], [25].
During five months of treatments and one month after stopping add-back therapy, the endometrium was rather thicker in group A than group B (p=0.022). This finding suggests that short-term (less than six months), low-dose estrogen therapy is not strongly associated with endometrial proliferation. In all except three patients, the endometrium was within the normal range of thickness (3–9mm) and showed even sonographic echo. In two patients on a low-dose estrogen-only regimen, the endometrial thickness was estimated to be 18mm and 19mm, and there was one patient with an increased endometrial thickness (17mm) in the tibolone group. The three women with increased endometrial thicknesses had no history of sexual contact and they declined invasive histologic evaluation of the endometrium. Their endometrial thicknesses were normalized after the next menstruation, as evidenced by ultrasonography (4mm, 7mm and 5mm, respectively), and therefore biopsies were not performed.
In the current study, we began add-back therapy from the second injection of GnRHa when most of the patients experience hypoestrogenic symptoms, to increase the compliance of medications. During five months of estrogen-only add-back treatment, only five patients out of 61 complained of low abdominal discomfort or pelvic pain and the degree of pain was mild (mean value of VRS, 1.2±0.5). The incidence of hypoestrogenic symptoms, such as hot flashes and sweating, was not different between the two treatment groups (Fig. 2).
The incidence of uterine bleeding had no statistical significance between groups A and B over five months of add-back therapy (44.64% vs. 40.98%, p=0.25). In addition, we observed changes in the incidence of uterine bleeding with time in the two groups. The incidence of uterine bleeding in group B was lower from the second month after beginning add-back therapy compared to group A, although there was no statistical significance (at the sixth month, p=0.086) (Fig. 3).
The low-dose estrogen-only regimen as a short-term add-back therapy can be an efficacious and tolerable option to add-back therapy with tibolone during post-operative GnRHa treatment after surgery for endometrioma.
There were limitations in the current study with respect to randomization and small numbers of study groups. Also, bone mineral densitometry was not performed in this study as it is well-known that low-dose estrogen has a preventive effect on osteoporosis in postmenopausal women [15], [26], [27]. Nevertheless, this is the first report to evaluate the efficacy and tolerability of a short-term, low-dose estrogen-only add-back regimen compared with another regimen. Future larger prospective randomized controlled trials need to be conducted to confirm our preliminary findings.
Acknowledgement
None
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PII: S0301-2115(10)00414-8
doi:10.1016/j.ejogrb.2010.08.008
© 2010 Elsevier Ireland Ltd. All rights reserved.
Volume 154, Issue 1 , Pages 85-89, January 2011
