The use of hormone therapy for atypical endometrial hyperplasia

Endometrial cancer (ER) is the leading nosological form among oncogynecologic diseases, and two-thirds of patients belong to the I pathogenetic variant and have pre-cancerous changes - atypical endometrial hyperplasia (AHE). Current trends in the treatment of cancer and precancer are the use of organ-preserving methods, and existing approaches to the treatment of patients with atypical hyperplasia of the endometrium have different efficacy - from complete cure to relapse and further progression. Such a spread in performance indicators is associated with the biological characteristics of the pathological processes of the endometrium and requires the search for new prognostic markers. A biological marker that determines the aggressiveness of the pathological process in the endometrium and the effect of treatment can be the methylation of the ESR gene. In addition, in 15-40% of cases of endometrial cancer in the tumor, high genetic instability is observed, which is revealed by the result of the analysis of microsatellite markers - microsatellite instability (MSI +). This means that the genes of DNA repair enzymes can be mutant. It is suggested that MSI develops with benign pathology of the endometrium and promotes the progression of the disease, which requires further study.

Thus, the determination of the relationship between the efficacy of the treatment of atypical hyperplasia of the endometrium and the underlying molecular lesions opens the prospect of identifying new markers for improving the results of therapy and preventing endometrial carcinoma.

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

67 patients with atypical hyperplasia of the endometrium were examined at the age of 35 to 69 years, the average age of which was 55.7 ± 5.3 years. Patients were divided into 3 groups: group 1 - patients with the presence of MSI (n = 15); group 2 - patients with methylation of the ESR gene (n = 22), group 3 - patients with the presence of MSI and methylation of the ESR gene (n = 10). The control group consisted of 20 patients with AGE without the investigated 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 procedure.

In all patients in the tissue, the polymerase chain reaction was used to study the presence of MSI + and methylation of the ESR gene. After isolation of DNA from the tissue (hyperplastic endometrium) by phenol method, methylation of the promoter region of the ESR gene was detected, for which the DNA was treated with methyl sensitive restriction enzymes. The presence of the MSI + genome was determined using the markers BAT 25 and BAT 26. The studies were carried out in the laboratory of Virola, Kharkov Medical Academy of Postgraduate Education. All patients underwent hormonal therapy according to the protocol according to the Protocol of the Ministry of Health of Ukraine from December 31, 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 investigation were processed according to the conventional methods of variation statistics using the x2-

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

Prior to treatment, the incidence of pre- and postmenstrual bloody discharge in the groups analyzed was initially different: the least frequent occurrence was found in the group of patients with both types of genetic disorders (30%) and more often in patients with methylation of the ESR gene (45% of cases).

Interim analysis of the effectiveness of the treatment showed a 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 less (the frequency of complaints decreased by 3 times).

The frequency of menorrhagia before the start of treatment ranged from 33.3% in patients with the presence of the MSI + phenotype to 50% in patients of the control group. The effect of treatment at 3 months was found in all patient groups (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 decreased significantly, but the efficacy fluctuations 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 beginning of treatment, lower abdominal pain associated with menstruation was observed in 20-31.8% of cases. Interim analysis of the effectiveness of the treatment showed a positive trend in all groups of patients, except for patients with the presence of MSI +. At the same time, after 6 months in all groups, the effectiveness of treatment was noted: the frequency of complaints decreased in the control group 5-fold; in the group with an epigenetic disorder of the ESR gene, 3.5 times; and in patients with MSI + and with both types of genetic disorders of the lower abdomen associated with menstruation, disappeared.

Lower abdominal pain, not associated with menstruation, was less common than with menstruation, and their frequency ranged from 13.3% (group 1) to 20.0% (group 3). Evaluation of the results of therapy at 3 months from its beginning revealed a positive result in all groups of patients, except for patients having a combination of MSI + with methylation of the ESR gene. After the end of treatment, its effectiveness was noted in all groups of patients and was characterized by the disappearance of lower abdominal pains not associated with menstruation, except for patients who had a violation of the ESR gene function, in which the incidence of this symptom decreased 3-fold.

Thus, the analysis of the clinical efficacy of hormone therapy in patients with reproductive and perimenopausal age with atypical hyperplasia of the endometrium, depending on the presence of MSI + and the violation of the function of the ESR gene, made it possible to establish a number of trends. First, most patients of all groups had a similar frequency of complaints prior to treatment. Differences consisted in the rates of menorrhagia and, to a lesser extent, pain in the lower abdomen. However, these symptoms did not depend on the analyzed genetic disorders. Secondly, the analysis of the effectiveness of treatment, conducted through 3 months, showed that at this stage there is a clear tendency to reduce the frequency of typical symptoms. This trend continues for the next months of treatment. Therefore, an intermediate analysis of the effectiveness of treatment is an important stage of therapy, which must be carried out to determine and correct further tactics. Third, in patients with reproductive and perimenopausal age with atypical hyperplasia of the endometrium, the effectiveness of treatment was different in the groups analyzed. The greatest decrease in the frequency of symptoms was observed in the control group of patients, and in the other groups the efficacy was lower by 1.5-3 times and also depended on the type of genetic disorder. Thus, the lowest decrease in the frequency of symptoms was observed in the group of patients having 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.

Analysis of the effectiveness of treatment in patients of reproductive age shows that there were no relapses in the control group. The presence of epigenetic disorder in ESR gene patients worsened the results of treatment, and in 28.6% of cases the relapse of atypical hyperplasia of the endometrium 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 the impaired function of the ESR gene, slightly better results were achieved. It is incorrect to speak about the reliability of the results obtained because of the small number of patients with microsatellite genome instability or the combination of MSI + with the methylation of the ESR gene. However, in general, for women of this age period, the development of their genetic disorders is characterized by a significant decrease in the effectiveness of hormone therapy.

Patients in the perimenopause reacted worse to the treatment methods used. Thus, the frequency of recurrence 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. Relatively worse results were obtained in the groups of patients with microsatellite instability of the genome (60.0% of cases of relapses, p <0.05) and in combination with MSI + with methylation of the ESR gene (66.7% of relapses, p <0.01 ). In patients with a violation of ESR gene expression, treatment results were 2.3 times worse than those in the control group (p> 0.05). The characteristics of women of this age group include not only a significant difference in the frequency of recurrence of atypical endometrial hyperplasia depending on genetic factors, but also a significant percentage - in more than half of the cases, relapses and progressions of atypical hyperplasia in endometrial carcinoma were noted.

The number of patients with atypical endometrial hyperplasia in menopause in the analyzed groups was small, which does not allow to speak about the reliability of the results. However, the trends identified in this age group coincide with the results obtained in patients of other age groups. In this connection, we can say with good reason that there is a correlation between the frequency of relapses and genetic disorders. In particular, in the control group, the frequency of recurrence of atypical endometrial hyperplasia was minimal. The worst results were obtained in groups of patients with the MSI + phenotype and in the case of a combination of microsatellite instability with the epigenetic disorder of the ESR gene. The results of treatment of patients with methylation of the ESR gene were 2 times worse than those of the control group.

Thus, the analysis shows significant fluctuations in the rates of recurrence and progression of the disease in patients with atypical hyperplasia of the endometrium, the results of treatment depending on the age and the presence of the patient's MSI + and / or methylation of the ESR gene. Women of reproductive age received the best results of treatment. With age, the frequency of recurrences and progressions of the disease in patients increased. However, the presence of microsatellite instability in the genome, epigenetic disruption of the ESR gene, or a combination thereof, decreases the effectiveness of the treatment. This dependence is observed in women of all age groups and has a clear connection with the type of disorder. In particular, a violation of the expression of the ESR gene leads to a significant increase in the frequency of recurrence of atypical endometrial hyperplasia (3-fold compared with the control group, p <0.01). Diagnosis of microsatellite instability of the genome in patients is accompanied by an even larger (1.4 times compared with patients with methylation of the ESR gene) by an increase in the number of relapses and progressions of the disease. The combination of MSI + patients and methylation of the ESR gene slightly reduced the efficacy of the treatment 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 genetic disorder in the form of MSI +, methylation of the ESR gene or their combination in patients with atypical hyperplasia of the endometrium, greatly reduces the effectiveness of standard hormone therapy. Such a decrease in the effectiveness of treatment may be due, in our view, to the following aspect. These genetic disorders affect not only the development and effectiveness of treatment of atypical hyperplasia, but also are factors in the progression of endometrial hyperplasia without atypia atypical and, subsequently, in carcinoma.

The conducted researches allow to draw the following conclusions.

The presence in patients with atypical hyperplasia of the endometrium of microsatellite instability of the genome, the methylation of the ESR gene, or their combination, has no characteristic clinical manifestations.
Reduction in the frequency and severity of clinical manifestations of atypical hyperplasia of the endometrium in the process of hormone therapy can be used as an auxiliary criterion in assessing its effectiveness.

Regardless of the age of patients, the efficacy of standard hormone therapy for atypical hyperplasia of the endometrium is reliably reduced when diagnosed in MSI + patients, methylation of the ESR gene or a combination thereof.

The high incidence of recurrence and progression of atypical endometrial hyperplasia when hormone therapy is used in patients with MSI + or a combination of MSI + with the methylation of the ESR gene requires timely correction of therapy or use of more radical therapies.

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