Preoperative treatment of uterine fibroid
The work presents a comparative evaluation of the efficacy of the administration of agonists of gonadotropin-releasing hormones and synthetic selective modulators of progesterone receptors as preoperative preparation of patients with uterine fibroids.
S.A. Levakov, Doctor of Medical Science, Professor,
N.A. Sheshukova, Professor,
O.V. Bolshakova, Candidate of Medical Science
I.M. Sechenov First Moscow State Medical University (State Budget Educational Institution of Higher Vocational Education), Moscow, Russia, 119991
City Clinical Hospital No.5 (Budgetary Public Health Facility), Moscow, Russia, 107014
Summary
Objective: A comparative evaluation of the efficacy of administration of agonists of gonadotropin-releasing hormones and synthetic selective modulators of progesterone receptors as preoperative preparation of patients with uterine fibroids.
Materials and Methods: 73 patients of reproductive age with uterine fibroids who underwent preoperative hormonal preparation were included in the study.
Conclusions: Buserelin-depo produces a more significant effect on the structure of myomatous nodules and enables to quickly reverse clinical symptoms of menstrual disorders which occur in patients with uterine fibroids. Synthetic selective modulators of progesterone receptors have some features that limit their widespread use, i. e. the need for daily administration of the drug, the lack of proper quick effect on myometrial structures, insufficient efficacy in patients with the combined uterine pathology etc.
Key words: agonists of gonadotropin-releasing hormones, synthetic selective modulators of progesterone receptors, uterine fibroid.
Uterine fibroid is a benign, usually multiple tumor composed of immature myocytes of vessel walls. Uterine fibroid is the most common disease in women of late reproductive age accounting, according to different authors, for 10 to 30% [1, 2].
The treatment of patients with uterine fibroid depends on the location, size, rate and the character of the growth of myomatous nodules, clinical and morphological variant of the tumor and other factors [1]. The pathogenetically justified concept of the treatment of uterine fibroids is the combined medical and surgical approach. Literature widely discusses the issue of the sequence of these methods, the duration of hormonal therapy and the drug choice.
The efficacy of the hormonal therapy may be different as it depends on the nature of hormonal disturbance and the presence and density of receptors in myomatous nodules and myometrium. Receptors predominate in myomatous nodules of small size consisting mainly of smooth muscle cellular component. As a rule, hormonal receptors are absent in tumors where the stromal component predominates as well as in large size nodules and in case of secondary ischemic degenerative changes, so the hormonal therapy may be ineffective [3].
The main goal of the drug therapy is reduction in the severity of clinical symptoms, restoration of fertility, and preservation of menstrual function. It involves the administration of the following groups of drugs: progestagens, agonists of gonadotropin-releasing hormones (GnRH), selective modulators of progesterone receptors (SMPR).
The possibility of use of the organ preserving treatment in patients with uterine fibroids defines the relevance of the complex medical measures: preoperative hormonal therapy, myomectomy and hormonal correction in the postoperative period for indications.
Objective of the study
Comparative evaluation of the efficacy of GnRH agonists and synthetic selective modulators of progesterone receptors as preoperative preparation of patients with uterine fibroids.
Materials and methods
The study included 73 patients of the late reproductive age; the mean age was 42 ±1.2.
The criteria for inclusion of patients in the study: uterine fibroid with intramural and/ or subserous localization of myomatous nodules with a diameter of more than 8 cm; menstrual disorders by type of menorrhagias, menometrorrhagias leading to anemization; the patient’s desire to save the menstrual and reproductive function; the absence of severe endocrine and somatic pathology (stage III impaired fat metabolism, bronchial asthma, diabetes, etc..), the availability of patient’s informed consent to hormonal therapy followed by surgery.
The study did not include patients with a history of the previously performed myomectomy; the presence of three or more myomatous nodules as well as submucous localization of nodules, patients with severe anemia; acute inflammation of the pelvic organs; previous oncological diseases; tumor-like and tumoral diseases of ovaries in the history or at the time of the study.
All the patients included in the study were divided into 2 groups. Group I was composed of 33 women who in the preoperative period underwent hormonal therapy with the drug Buserilin-depo: 3.75 intramuscularly every 28 days, the overall course of the treatment was 2-3 injections.
Group II included 30 women who received Ulispristal acetate (Esmiya) for the preoperative preparation at a dose of 5 mg orally once a day for 3 months.
The patients in the both groups were comparable in terms of the parity of pregnancies, previous gynecological and somatic diseases, and the duration of the presence of uterine fibroid.
All the patients had mild to moderate anemia. The mean level of hemoglobin was 99±2.8 g/L, the mean concentration of iron in the serum was equal to 8.3 µmol/L.
Before the administration of hormonal therapy the state of endometrium and myometrium was evaluated. For this purpose, ultrasound examination with the use of a convex probe with a frequency of 3.5 MHz (transabdominal investigation) and with a frequency of 5 - 8 MHz (transvaginal investigation) was performed. The ultrasound examination of the pelvic area was carried out in the longitudinal, transverse, and oblique projections. When viewing in the "gray scale", the size of the uterus, the volume, structure, and localization of visualized nodules, condition of uterine cavity, cervix and uterine appendages were analyzed. Peculiarities of vascularization were assessed using the color doppler imaging.
The size of myomatous nodules in the women under study was in the range of 80 mm to 120 mm, the preferential localization on the posterior wall (17.8%), in the bottom (16.4%) and on the right edge of the uterus (20.5%). Two myomatous nodules were observed in 5 patients (15.1%) of Group I and 4 women (13.3%) of Group II.
All patients before the start of the combined treatment underwent separate diagnostic curettage of uterus under the control of hysteroscopy followed by morphological examination of scraped material from cervical canal and uterine cavity. Simple endometrial hyperplasia without atypia was diagnosed in 6 patients (18.1%) of Group I and in 4 women (13.3%) of Group II. In 3 women of Group I (9.8%) and in 2 women (6.6%) of Group II, uterine fibroid was combined with adenomyosis.
The efficacy of the treatment was evaluated on the basis of the data of clinical manifestations of the disease as well as using measurements of myomatous nodules by means of ultrasound examination.
Results of the conducted investigations
3 months after the start of the treatment, the absence of clinical symptoms of menstrual disorders was observed in all of the women of Group I and in 76.6% of the patients of Group II. 1 month after injection of Buserelin-depo the "breakthrough" bleeding occurred in 6 women (18.1%) of Group I; symptomatic treatment was administered to stop it. In 12 patients (40.0%) of Group II bloody discharge of moderate and insignificant intensity remained within 1-2 months.
The level of hemoglobin against the background of hormonal therapy in the both groups was at least 100 g/l.
While analyzing the average diameter of myomatous nodules after the hormonal therapy using the ultrasound examination, a decrease in this indicator by 51.5% in patients of Group I and by 26.6% in the patients of Group II was found.
In 23 patients (84.8%) administering Buserelin-depo, a decrease of the median endometrial thickness up to 4-5 mm was observed, in 2 women (6.0%) this figure was 5-6 mm. In the group of the patients treated with ulipristal acetate, the following data were observed: a decrease in size of endometrium of less than 8 mm was observed in 18 patients (60%). Only in 7 cases (23.3%), an increase in the studied index to 12 and 14 mm was recorded. While performing the ultrasound examination prior to hormonal therapy, it was found that the endometrial thickness was 7 and 8 mm, respectively.
The patients of Group II who had pathological changes in the endometrium according to the data of the ultrasound examination underwent cytological examination of the aspirate from the uterine cavity.
We did not note in any observation the presence of significant adverse effects during preoperative hormonal treatment which could require cessation of the therapy. The most common complaints of the patients of Groups I and II were vegetative disorders as well as mild to moderate flushes not requiring any drug correction.
The second phase of the complex treatment of uterine fibroid, the surgery in the form of myomectomy, was carried out upon completion of the hormonal preparation: a month after the third injection of Buserelin-depo or after a three month administration of Ulipristal acetate.
The organ-preserving surgery was not associated with any technical difficulty in Group I and in Group II. The surgery without uterine cavity opening was performed in 23 patients (69.6%) of Group I and in 9 patients (30%) of Group II; in the remaining women myomectomy was performed by entering the uterine cavity. The intraoperative blood loss did not exceed 120 ml on an average, postoperative complications were not observed in the both groups.
All removed myomatous nodules were examined by pathomorphologists. In all the patients, the changes in myomatous nodules were benign, 2 women of Group II had proliferative uterine fibroids. No fundamental differences between the groups were revealed in the analysis of the results of histological examination.
Discussion
The administration of hormonal drugs in the monotherapy of uterine fibroids is not only insufficiently effective but also has some limitations due to a high incidence of combined uterine pathologies, the presence of significant adverse effects and contraindications, especially in patients in the late reproductive and perimenopausal period. And to date, the main and the only method of treatment of uterine fibroids independent of patient’s age is the surgical method.
In the present study, we used a comprehensive approach to the treatment of uterine fibroid in patients who wish to preserve the menstrual and reproductive function. We have carried out a comparative evaluation of the efficacy of GnRH agonists and selective modulators of progesterone receptors in the preoperative therapy of uterine fibroid and have made the following conclusions.
Administration of Buserelin-depo and Ulipristal acetate leads to fast reversal of clinical symptoms of menstrual disorders that occur in patients with uterine fibroids and prevents the progression of anemia. Longer existing bloody discharge in patients of Group II were not intense and did not contribute to further anemization of women.
Comparing the effect of the two drugs on the size of myomatous nodules, we can confidently confirm that Buserelin-depo has a more profound effect on the structure of fibroids than Ulipristal acetate as during the administration of GnRH agonist the average diameter of nodules reduced almost twofold. Our findings do not contradict the literature data. The reduction in size of the uterus tumor before the planned surgery significantly improves the outcomes of the surgery leading to the possibility of the choice of a surgical access which is the most preserving to a woman and intraoperative reduction of blood loss. In addition, a pronounced decrease of the diameter of myomatous nodules allows you to reduce the time of preoperative preparation with the help of the drug Buserilin –depo up to 1-2 injections. The recommended duration of the administration of Ulipristal acetate in the preoperative period (considering its mechanism of action) is at least 3 months.
Progesterone antagonists may cause the development of endometrial hyperplasia. Taking into account the high frequency of the combination of uterine fibroids with adenomyosis and endometrial hyperplastic processes, indications for administration of Ulipristal acetate are limited, especially in patients with the combined pathology. One of the contraindications to the administration of Ulipristal acetate is the presence of bleeding for reasons unconnected with uterine fibroid.
In our study, 23.3% of the patients had an increase of endometrium during the Ulipristal acetate therapy, which was determined by the ultrasound examination. In the works carried out by foreign authors, it is assumed that these changes are weakly associated with the proliferation which is determined histologically. It is believed that this may be due to the swelling of the myometrium and underlying connective tissue, formation of cysts, accumulation of fluid in the lumen of dilated glands or the presence of a benign thickening of the stroma because of increasing the formation of collagen in its cells (Liedman et al., 2000; Baird et al., 2003, Nathalie Chabbert-Buffet 2005). However, this data require additional researches and should be verified morphologically.
By analyzing the frequency of occurrence of the adverse effect which is most common at the stage I of the combined treatment of patients with uterine fibroids (mild to moderate flushes), it was found that when administering Buserelin-depo and Ulipristal acetate, they were observed with the same frequency. The available literature data show that GnRH agonists significantly reduce estrogen levels, which is accompanied by the risk of reduction of mineral density of bone tissue and flushes. However, it should be noted that the severity of adverse effects is directly dependent on the duration of the treatment with GnRH agonists, especially in patients of the reproductive age.
Thus, summing up the results of our study to assess the efficacy of hormonal therapy as a preoperative treatment of uterine fibroids in women of the late reproductive age, we can draw up the following conclusions. In spite of the fact that in recent years selective modulators of progesterone receptors were the object of active researches, this group of drugs is used in the preoperative preparation of patients with uterine fibroids only for a short time, and they have a number of characteristics which limit their widespread use, i.e. the need for daily administration of drugs, lack of adequate rapid effect on the structure of myometrium, lack of the efficacy in patients with the combined uterine pathology and others. Therefore, to date, Ulipristal acetate cannot be recommended as an alternative to the use of GnRH agonists.
Buserelin-depo remains one of the most studied, effective and widely used hormonal drugs as a preoperative and postoperative therapy in patients with uterine fibroid including those with the combined pathology of endometrium and myometrium, which is an additional advantage of this drug. GnRH agonists exert their effect not only due to the suppression of the hypothalamic-pituitary-ovarian system but also due to local effects on the tissue. By binding to their own receptors, they are capable of reducing the production of aromatase, synthesis of connective tissue, blocking the production of various factors of growth and cytokines as well as influencing the processes of apoptosis induction [4].
References:
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2. E.M. Vikhlyeva. Guidelines of diagnosis and treatment of uterine leiomyoma. MedPress, - 2004.- 400 p.
3. Practice guidelines of clinical gynecology. Under the editorship of I.S. Sidorova, T.V.Ovsyannikova.- М., 2006 -446 p.
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