| Background and objectiveCervical cancer and ovarian malignancy are common gynecological malignancy.In recent 20 years,with the improvement of diagnosis and treatment level,the incidence of cervical cancer and ovarian malignancy has been increasing,and the younger trend is very obvious.With the continuous progress of diagnosis and treatment technology,the quality of life of patients after chemotherapy has been paid more and more attention by gynecologists.Due to the poor targeting of chemotherapy drugs,killing tumor cells will damage the normal tissues and cells of the human body at the same time,such as destroying the follicle cells in the growth and development period of female ovarian tissue,resulting in premature ovarian dysfunction(Premature Overy Insufficiency,POI)of patients.The main clinical manifestation of POI is infertility.Other clinical symptoms include a higher mortality rate in patients with POI than in women with natural amenorrhea.Affecting cognitive function:Patients with early amenorrhea are at higher risk of dementia;Affect mental health:patients are more prone to depression,anxiety,somatic symptoms,hostility,sensitivity and other psychological distress,which reduces the overall well-being and satisfaction;Sexual dysfunction:reduced sexual desire,reduced sexual frequency,increased pain;Cardiovascular disease:Studies have shown that patients with POI have a higher risk of ischemic heart disease than patients with natural amenorrhea;Bone mineral density was significantly lower in osteoporosis patients;Affect the average life span and so on.Female ovarian function injury caused by chemotherapy has a great impact on the general quality of life of the patients,and more than 60%of female patients have ovarian function injury after chemotherapy.Therefore,it is urgent to explore a treatment plan to solve the ovarian dysfunction of young women after chemotherapy.Fertility conservation function of gynecological malignancies includes surgical treatment with fertility conservation and related reproductive endocrine therapy.For example,the biggest advantage of extensive cervix resection for cervical cancer is that it can preserve the patient’s fertility function while treating cervical cancer.However,the surgical indications are as follows:(1)the patient has strong fertility requirements;(2)The pathological diagnosis and clinical staging of cervical cancer were determined preoperatively.Colposcopy examination found no tumor infiltration above the cervical internal opening,and MRI examination found no regional lymph node metastasis.(3)Cervical cancer is only suitable for early cervical cancer.For cervical cancer with tumor size of>2cm and/or involving blood vessels and lymphatics stage IB2 and above,postoperative recurrence is easy,so extensive cervical resection is not suitable.For epithelial ovarian cancer,the indications for fertility preservation surgery are more stringent:(1)patient desire to procreate;(2)The operative pathological stage was Ⅰa,and the degree of pathological differentiation was highly differentiated;(3)At the stage of surgery,no "high areas"were found,including uterorectal depression,lateral colon sulcus,mesentery,omentum greater and retroperitoneal lymph node biopsy,and no metastases were found.A large number of young women suffering from gynecological malignancies are unable to perform simple fertility conservation surgery,but they can still perform the fertility conservation program of surgery+chemotherapy+reproductive endocrine therapy.Reproductive endocrine therapy with reproductive function preservation includes embryo freezing,oocyte freezing,ovarian suppression,ovarian tissue freezing and transplantation,etc.The application of reproductive endocrine therapy depends on the patient’s age,pathological diagnosis,treatment method,marriage,and the wishes of the patient and family members.Assisted reproductive technology is still in the experimental stage,the only clinical application of embryo cryopreservation-autologous transplantation is facing ethical problems.Ovarian transplantation has a good clinical effect on the protection of ovarian function,but there is a risk of tumor recurrence,which requires strict control of the use of indications,and has not been popularized in clinical practice.Because some reproductive endocrine therapy regimens may delay oncology treatment,it is emphasized that gynecologic oncologists and gynecologic endocrinologists assist in the diagnosis and treatment to minimize the risk of delayed oncology treatment while preserving reproductive function.GnRHa is an artificial synthetic gonadotropin-releasing hormone agonist,which is a commonly used method of ovarian inhibition.GnRHa is synthetic gonadotropin-releasing hormone agonist,is a common ovarian suppression method,the main mechanism is based on the inhibitory effect of hypothalamic-pituitary-ovarian axis,inhibit the secretion of pituitary FSH,thus inhibiting the rise of FSH,inhibit the initial raising of ovarian follicle and circulation to raise,the follicle at the follicular phase before the primitive follicles and sinus,makes the ovaries at the early stage of the youth or menopausal status,at the same time,low estrogen decreased ovarian tissue blood perfusion,which reduces the chemotherapy drugs in ovarian accumulated concentration,ovarian protection effect.Prospective clinical studies of breast cancer showed that gonadotropin releasing hormone agonist(GnRHa)can effectively protect ovarian function injury caused by chemotherapy and reduce the incidence of POI.However,there are few prospective clinical studies on the protection of ovarian function by GnRHa in gynecological malignant tumor patients.Because the chemotherapy regimens for breast cancer are different from those for cervical cancer and ovarian cancer,whether GnRHa has a protective effect on the ovarian function injury caused by chemotherapy in patients with cervical cancer and ovarian cancer is still in the exploratory stage.In this clinical study,a prospective cohort study was conducted to evaluate the protective effect of gonadotropin-releasing hormone agonist on ovarian function impairment in patients with chemotherapy-induced early cervical cancer and ovarian malignancy.Materials and methodsPatients with early cervical cancer and early ovarian malignancies(epithelial malignancies,germ cell malignancies,granulose-cell tumors)who received gynecological chemotherapy in the First Affiliated Hospital of Zhengzhou University from January 2018 to December 2020 were included,and the diagnosis and treatment process and case data were recorded in detail.The patients were divided into control group and GnRHA group according to different treatment regimens.The enrolled patients voluntarily participated in this study and signed the informed consent.This study has been approved by the Medical Ethics Committee of the First Affiliated Hospital of Zhengzhou University(2018-KY-41)and registered in the Chinese Clinical Trial Registry(ChiCTR1800019114).Two clinical researchers independently collected and collated relevant data,and long-term follow-up was conducted on the patients" general physical condition(36-items short form health survey)and menstrual condition(KMI perimenopausal symptom score).Changes in serum levels of FSH,E2,AMH and other hormones before and during chemotherapy,3 months and 6 months after chemotherapy were measured in the two groups,and SPSS 21.0 statistical software was used for data analysis.The measurement data was expressed as mean±standard deviation(x±s).The t-test was used to compare the two groups of data,and the analysis of variance of repeated measurements was used to compare the data at multiple time points.Further,the LSD-t test was used for pair comparison.Enumeration data were expressed as frequency and rate(%),and χ2 test was used for comparison between groups.P<0.05 was considered statistically significant.Results1.Before chemotherapy,serum levels of FSH,FSH/LH,AMH and E2 in two groups were all within the normal range.FSH in the GnRHa group was 3.43±0.87ng·L"-1,FSH in the control group was 4.34±0.56ng·L-1,E2 in the GnRHa group was 89.36±24.10IU·L-1,E2 in the control group was 95.44±20.71IU·L-1,and AMH in the GnRHa group was 5.46±1.15 μg·L-1.The serum AMH of the control group was 5.34±1.73 μg·L-1,and there was no significant difference between the two groups(P>0.05).There was no significant abnormality in general physical condition and menstruation of the two groups(P>0.05).2.During chemotherapy,with the progress of chemotherapy course,the serum FSH value and FSH/LH value in both groups continued to increase,and the serum E2 and AMH levels in both groups decreased to varying degrees,with significant difference in the degree of change between the two groups(P<0.05),which usually reached the lowest value at the end of chemotherapy process.On the other hand,with the increase of chemotherapy course,the increase degree of serum FSH and FSH/LH in the control group was significantly higher than that in the GnRHa group,and the decrease degree of serum AMH and E2 in the control group was significantly higher than that in the GnRHa group,with statistical significance(P<0.05).During chemotherapy,the two groups of patients presented different degrees of menstruation,amenorrhea and other symptoms(P<0.05).3.Three months after the end of chemotherapy,the serum hormone levels of patients in the two groups were reexamined.The serum FSH of the GnRHa group was 12.17±1.54ng·L-1,the serum FSH of the control group was 26.54± 4.53ng·L-1,the serum E2 of the GnRHA group was 48.96±13.94IU·L-1,the serum E2 of the control group was 27.50±10.05IU·L-1,the serum AMH of the GnRHa group was 2.02±0.65 μg·L-1,and the serum AMH of the control group was 0.76±0.14μg·L-1.By comparing the data of the two groups,the serum FSH level of the GnRHAa group was significantly lower than that of the control group,the difference was statistically significant(P<0.05),and the serum E2 and AMH levels of the GnRHa group were significantly higher than that of the control group,the difference was statistically significant(P<0.05).4.Serum hormone levels in both groups were re-examined 6 months after the end of chemotherapy.The serum FSH of the GnRHa group was 6.12±1.40ng·L-1,the serum FSH of the control group was 16.62±3.70ng·L-1,the serum E2 of the GnRHa group was 96.53±18.89IU·L-1,the serum E2 of the control group was 44.61±13.54IU·L-1,the serum AMH of the GnRHa group was 4.17±1.97μg·L-1,and the serum AMH of the control group was 1.98±0.44μg·L-1.By comparing the data of the two groups,the serum FSH level in the GnRHa group basically returned to the pre-chemotherapy level,and was significantly lower than that in the control group,with statistical significance(P<0.05).The serum E2 and AMH levels in the GnRHa group basically returned to the pre-chemotherapy level,and were significantly higher than that in the control group,with statistical significance(P<0.05).5.After chemotherapy,the natural menstrual recovery time in the GnRHa group[(3.6±1.4)months]was significantly shorter than that in the control group[(5.5±1.7)months](t=10.817,P<0.001).The proportion of natural menstruation in the GnRHa group was 93.3%,which was significantly higher than that in the control group(71.1%),the difference being statistically significant(P<0.05).The proportion of sparse menstruation in the GnRHa group was 14.3%,which was significantly lower than that in the control group(43.8%),the difference being statistically significant(P<0.05).6.Six months after the end of chemotherapy,the average SF-36 score in the GnRHa group was 430.28±15.16,and that in the control group was 406.74±21.08.The average SF-36 score in the GnRHa group was higher than that in the control group,the difference being statistically significant(P<0.001).The mean KMI menopausal index score of patients in the GnRHa group was 2.14±0.58,and that of patients in the control group was 8.94±3.76.The mean KMI score of patients in the GnRHa group was lower than that of the control group,and the difference was statistically significant(P<0.001).ConclusionChemotherapy combined with Gonadotropin-releasing hormone analogue agonist(GnRHa)can effectively prevent ovarian function injury in patients with early cervical cancer and ovarian cancer treated with chemotherapy,and significantly improve the quality of life of patients,and reduce the symptoms of perimenopausal period.Compared with other research plan of the reproductive toxicity of chemotherapy protection,chemotherapy combined use of acetic acid goserelin slow-release implants to treat limited by economic and medical technology level is low,does not affect chemotherapy regimens,has high clinical value,but still need to the research results of the clinical data of the multicenter,large sample confirmed acetate goserelin slow-release implants the effectiveness of the treatment. |
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