Use of hormone therapy in atypical endometrial hyperplasia

Endometrial cancer (EC) is the leading nosological form among oncogynecological diseases, and two thirds of patients belong to the first pathogenetic variant and have precancerous changes preceding this process - atypical endometrial hyperplasia (AGE). Modern trends in the treatment of cancer and precancer consist in the use of organ-preserving methods, and existing approaches to the treatment of patients with atypical endometrial hyperplasia have different effectiveness - from complete cure to relapse and further progression. Such a spread in efficiency indicators is associated with the biological characteristics of pathological processes in the endometrium and requires a search for new prognostic markers. Methylation of the ESR gene can be a biological marker that determines the aggressiveness of the pathological process in the endometrium and the effect of treatment. In addition, in 15-40% of endometrial cancer cases, the tumor has high genetic instability, which is revealed by the result of the analysis of microsatellite markers - microsatellite instability (MSI+). This means that genes of DNA repair enzymes may be mutant. It is assumed that MSI develops in benign endometrial pathology and contributes to the progression of the disease, which requires further study.

Thus, determining the relationship between the effectiveness of treatment of atypical endometrial hyperplasia and the underlying molecular damage opens up prospects for identifying new markers to improve the results of therapy and prevention of endometrial carcinoma.

The aim of the study was to investigate the clinical efficacy, recurrence rate and progression of atypical endometrial hyperplasia using hormone therapy in patients depending on age, the presence of MSI and methylation of the ESR gene.

A total of 67 patients with atypical endometrial hyperplasia aged 35 to 69 years were examined, the average age was 55.7±5.3 years. The patients were divided into 3 groups: group 1 - patients with MSI (n = 15); group 2 - patients with methylation of the ESR gene (n = 22), group 3 - patients with MSI and methylation of the ESR gene (n = 10). The control group consisted of 20 patients with AGE without the studied gene disorders. The diagnosis in all cases was verified morphologically after diagnostic curettage and/or hysteroscopy with targeted biopsy. Histological examination of tissues was carried out in accordance with the standard technique.

In all patients, the presence of MSI+ and methylation of the ESR gene were studied in the tissue using the polymerase chain reaction method. After DNA was isolated from the tissue (hyperplastic endometrium), methylation of the promoter region of the ESR gene was detected using the phenol method, for which the DNA was treated with methyl-sensitive restriction enzymes. The presence of the MSI+ genome was determined using the BAT 25 and BAT 26 markers. The studies were conducted in the Virola laboratory of the Kharkiv Medical Academy of Postgraduate Education. All patients underwent hormone therapy according to the scheme according to the Protocol of the Ministry of Health of Ukraine dated 31.12.2004, No. 676. The effectiveness of hormone therapy was assessed by the frequency of complaints, relapses and progressions of the disease. The data obtained as a result of the study were processed using generally accepted methods of variation statistics using the χ2- criterion.

The obtained data on the clinical efficacy of hormone therapy in reproductive and perimenopausal patients with atypical endometrial hyperplasia depending on the presence of MSI+ and ESR gene methylation showed that the frequency of acyclic bloody discharge before treatment was approximately the same in percentage terms regardless of the presence of microsatellite instability, epigenetic disorder of the ESR gene or both types of genetic disorders in patients. After 3 months of treatment, the frequency of acyclic bloody discharge in the control group of patients and in the presence of both types of disorders decreased by 1.5 times, in the presence of MSI+ in women - by 1.25 times and in the group with ESR gene methylation - by 1.4 times. After the end of treatment, the analyzed symptom was detected much less frequently, and the greatest clinical effect was noted in the control group of patients (the frequency of complaints decreased by 6 times). In other groups of patients, the frequency of acyclic bloody discharge decreased to a lesser extent and depended on the type of genetic changes. The best clinical effect was achieved in patients with epigenetic disorders of the ESR gene (the frequency of complaints decreased by 3.5 times), and the worst - in the group of patients with a combination of the MSI+ phenotype and impaired expression of the ESR gene (the frequency of complaints decreased by 1.5 times).

Before the start of treatment, the frequency of pre- and postmenstrual bleeding in the analyzed groups initially differed: bleeding occurred least often in the group of patients with both types of genetic disorders (30%) and more often in patients with the presence of methylation of the ESR gene (45% of cases).

Interim analysis of the effectiveness of the treatment showed clear positive dynamics in all groups of patients. After completion of therapy, the best effect was obtained in the control group and group 2 - the frequency of complaints decreased by 8 and 5 times, respectively. The effectiveness of treatment of patients with microsatellite instability (group 1) or both types of genetic disorders (group 3) was lower (the frequency of complaints decreased by 3 times).

The frequency of menorrhagia before treatment varied from 33.3% in patients with the MSI+ phenotype to 50% in patients in the control group. The effect of the treatment after 3 months was found in all groups of patients (from 1.25 times in the presence of the MSI+ phenotype to 2.5 times in the control group). After completion of treatment, the frequency of menorrhagia significantly decreased, but the fluctuations in effectiveness were also significant. The greatest effect was noted in the control group and in patients of group 1 (the frequency of menorrhagia decreased by 10 and 5 times, respectively).

Before the treatment, lower abdominal pain associated with menstruation was observed in 20-31.8% of cases. Interim analysis of the effectiveness of the treatment showed positive dynamics in all groups of patients, except for patients with MSI+. At the same time, after 6 months, treatment effectiveness was noted in all groups: the frequency of complaints decreased in the control group by 5 times; in the group with epigenetic disorder of the ESR gene - by 3.5 times; and in patients with MSI+ and with both types of genetic disorders, lower abdominal pain associated with menstruation disappeared.

Lower abdominal pain not associated with menstruation was less common than with menstruation, and its frequency ranged from 13.3% (group 1) to 20.0% (group 3). Evaluation of the therapy results 3 months after its initiation revealed a positive result in all groups of patients, except for patients with a combination of MSI+ with methylation of the ESR gene. After completion of treatment, its effectiveness was noted in all groups of patients and was characterized by the disappearance of lower abdominal pain not associated with menstruation, with the exception of patients with a dysfunction of the ESR gene, in whom the frequency of this symptom decreased by 3 times.

Thus, the conducted analysis of the clinical efficiency of hormone therapy in patients of reproductive and perimenopausal age with atypical endometrial hyperplasia depending on the presence of MSI+ and dysfunction of the ESR gene allowed us to establish a number of trends. Firstly, most patients in all groups had a similar frequency of complaints before the start of treatment. The differences consisted in the frequency of menorrhagia and, to a lesser extent, lower abdominal pain. However, these symptoms did not depend on the analyzed genetic disorders. Secondly, the analysis of the treatment efficiency, carried out after 3 months, showed that at this stage there is a clear tendency to reduce the frequency of typical symptoms. This trend persists during the following months of treatment. Therefore, the intermediate analysis of the treatment efficiency is an important stage of therapy, which must be carried out to determine and correct further tactics. Thirdly, in patients of reproductive and perimenopausal age with atypical endometrial hyperplasia, the treatment efficiency was different in the analyzed groups. The greatest reduction in the frequency of disease symptoms was observed in the control group of patients, and in the other groups the effectiveness was 1.5-3 times lower and also depended on the type of genetic disorder. Thus, the smallest reduction in the frequency of symptoms was observed in the group of patients with a combination of microsatellite instability of the genome with a violation of the expression of the ESR gene.

Patients of reproductive age, regardless of the presence of MSI+ and methylation of the ESR gene, had better treatment outcomes.

The analysis of the treatment efficiency of patients of reproductive age shows that there were no relapses in the control group. The presence of epigenetic disorder of the ESR gene in patients worsened the treatment results, and in 28.6% of cases, a relapse of atypical endometrial hyperplasia was noted. The worst results were recorded in the group of patients with the MSI+ phenotype, and in the case of a combination of microsatellite instability of the genome with impaired function of the ESR gene in patients, slightly better indicators were achieved. It is incorrect to speak about the reliability of the obtained results due to the small number of patients with microsatellite instability of the genome or a combination of MSI+ with methylation of the ESR gene. However, in general, for women of this age period, with the development of genetic disorders, a significant decrease in the effectiveness of hormone therapy is characteristic.

Perimenopausal patients responded worse to the treatment methods. Thus, the recurrence rate of atypical endometrial hyperplasia in the control group was 22.2%. The development of genetic disorders in women was accompanied by a significant decrease in the effectiveness of treatment. Significantly worse results compared to the control were obtained in groups of patients with microsatellite instability of the genome (60.0% of recurrence cases, p < 0.05) and with a combination of MSI+ with methylation of the ESR gene (66.7% of recurrence cases, p < 0.01). In patients with impaired expression of the ESR gene, the treatment results were 2.3 times worse than in the control group (p > 0.05). The peculiarities of women in this age category include not only a significant difference in the frequency of relapses of atypical endometrial hyperplasia depending on genetic factors, but also their significant percentage - in more than half of the cases of observations, relapses and progression of atypical hyperplasia into endometrial carcinoma were noted.

The number of patients with atypical endometrial hyperplasia in menopause in the analyzed groups was small, which does not allow us to speak about the reliability of the results. However, the trends identified in this age category coincide with the results obtained in patients of other age groups. In this regard, we have more grounds to speak about the presence of a correlation between the frequency of relapses and genetic disorders. In particular, in the control group, the frequency of relapses of atypical endometrial hyperplasia was the lowest. The worst results were obtained in groups of patients with the MSI+ phenotype and in the case of a combination of microsatellite instability with epigenetic disorder of the ESR gene. The treatment results of patients with methylation of the ESR gene were 2 times worse than those in the control group.

Thus, the conducted analysis indicates significant variations in the incidence of relapses and disease progressions in patients with atypical endometrial hyperplasia, while the treatment results depend on the age and the presence of MSI+ and/or ESR gene methylation in the patient. The best treatment results were obtained in women of reproductive age. The incidence of relapses and disease progressions in patients increased with age. However, the presence of microsatellite instability of the genome, epigenetic disorder of the ESR gene, or their combination in patients reduces the effectiveness of the treatment. Such a dependence is observed in women of all age groups and has a clear connection with the type of disorder. In particular, impaired expression of the ESR gene leads to a reliable increase in the incidence of relapses of atypical endometrial hyperplasia (3 times compared to the control group, p < 0.01). Diagnosis of microsatellite instability of the genome in patients is accompanied by an even greater (1.4 times compared to patients with methylation of the ESR gene) increase in the number of relapses and disease progressions. The combination of MSI+ and ESR gene methylation in patients slightly reduced the treatment efficiency compared to the group of patients with only microsatellite instability of the genome (70.0 and 66.6% of relapses, respectively). The data obtained indicate that the presence of a genetic disorder in the form of MSI+, ESR gene methylation, or their combination in patients with atypical endometrial hyperplasia reduces the efficiency of standard hormone therapy many times over. Such a decrease in treatment efficiency may be due, in our opinion, to the following aspect. The above genetic disorders affect not only the development and efficiency of treatment of atypical hyperplasia, but are also factors in the progression of endometrial hyperplasia without atypia to atypical and then to carcinoma.

The conducted research allows us to draw the following conclusions.

The presence of microsatellite instability of the genome, methylation of the ESR gene or their combination in patients with atypical endometrial hyperplasia does not have characteristic clinical manifestations.
A decrease in the frequency and severity of clinical manifestations of atypical endometrial hyperplasia during hormone therapy can be used as an auxiliary criterion in assessing its effectiveness.

Regardless of the age of patients, the effectiveness of standard hormone therapy for atypical endometrial hyperplasia is significantly reduced when patients are diagnosed with MSI+, ESR gene methylation, or a combination of both.

The high frequency of relapses and progressions of atypical endometrial hyperplasia when using hormone therapy in patients with MSI+ or a combination of MSI+ with methylation of the ESR gene requires timely correction of therapy or the use of more radical treatment methods.

Prof. N. A. Shcherbina, M. A. Kartashova. Use of hormone therapy for atypical endometrial hyperplasia in patients with microsatellite instability and methylation of the esr gene // International Medical Journal - No. 4 - 2012