| ObjectivesBy observing the damage of cyclophosphamide(CTX)to ovarian function and influence to prognosis in patients with breast cancer after chemotherapy,we generalized the clinical traditional Chinese medicine(TCM)characteristics of ovarian dysfunction,and explore the correlation between the dosage of CTX and follicle-stimulating hormone(FSH),to provide a reference when evaluating the damage of ovarian function and offering syndrome differentiation treatment in early stage.Then effective treatment can be timely given to interrupt,delay or even reverse the progression of premature ovarian failure(POI),which is beneficial to the health of life and reproduction.MethodsA retrospective study was conducted in 156 patients with breast cancer who were younger than 40 years old and had received chemotherapy with CTX at the Department of Galactophore,First Affiliated Hospital,Guangzhou University of Chinese Medicine,from January 2010 to January 2019.All patients were divided into three groups with different degrees of ovarian dysfunction according to the basic level of FSH in the early follicle phase after the last chemotherapy:Pre-period POI Group contained patients with sub-clinical(10mIU/ml<FSH?25mIU/ml),POI in the early stage group(25mIU/ml<FSH?40mIU/ml),POI in the final stage group(FSH>40mIU/ml).By observing menses,symptoms related to perimenopause,tongue coating and pulse,collecting the levels of serum sexual hormones,as well as evaluating the scores of the Kupperman scale,we generalized the characteristics of TCM symptoms in these groups.Recovery of menses,the levels of serum sexual hormones,quality of life and reproduction were follow-up visited 1 year after chemotherapy.Statistical analysis was conducted between groups and inner groups.Results1.Based on the basic level of FSH after the last chemotherapy,we classify different damage degrees of ovarian dysfunction caused by CTX evaluating.A total of 156 patients were enrolled in the study,including 38 in the pre-period POI Group,27 in the POI in the early stage group,and 91 in the POI in the final stage group.(1)age group distribution:59.6%(93/156 cases)The age of onset of chemotherapy-induced ovarian function impairment was 35-39 years old,including 16 cases(42.11%)in the POI pre-stage group and 21 cases(77.78%)in the POI early group.There were 56 cases(61.54%)in the late POI group,and there was no significant difference in the age group between the three groups(P>0.05).(2)Fertility willingness:26 cases(68.4%)had prenatal requirements in the POI group,15 cases(55.6%)in the POI early group,and 36 cases(39.6%)in the POI late group.The fertility intention of the three groups was not significant.Difference(P>0.05).(3)Chemotherapy cycle and CTX dose:The total mean chemotherapy cycle was 6.48±1.88,and the median dose of total CTX chemotherapy was 3.4(2.4,3.6)g.There was no significant difference in the cumulative dose of CTX chemotherapy in the three groups(P>0.05).2.Menstrual performance:(1)Previous menstrual conditions:83.3%(129/155 patients)had normal menstruation,including 29 patients(76.3%)in the POI group,24 patients(88.9%)in the POI early group,and 76 patients(84.4%)in the POI late group;%(13/155 patients)had previous menstrual periods,including 7 patients in the pre-POI group(18.4%)(menstrual cycle was more than 37 days to February),and 1 patient in the early POI group(3.7%)(the menstrual cycle was more than 37).From February to February,5 patients(5.6%)in the POI late group(menstrual cycle mostly from 37 days to March);6.5%(10/155 patients)had premenstrual period;1 case(2.6%)in the POI pre-group 1 case(3.7%)in the early POI group and 8 cases(8.9%)in the POI late group;0.6%(1/155 cases)showed a decrease in menstrual flow,which was the late POI group(1.1%);0.6%(1/In 155 patients,the patients showed prolonged menstruation,which was in the pre-POI group(2.6%),and 0.6%(1/155 patients)showed no regular menstruation,which was the early POI group(3.7%).There were no significantdifferences in menstrual conditions between the three groups(P>0.05).(2)menstrual period during chemotherapy:patients with abnormal menstrual cycle,menstrual period,menstrual period and other aspects during chemotherapy.67.7%(105/155 patients)had late menstruation,including 27 patients(71.1%)in the POI group(menstrual cycle mostly from February to April),and 19 patients(70.4%)in the early POI group(the menstrual cycle was more than 37).From April to April,59 patients(65.6%)in the POI late group(menstrual cycle mostly from February to April);7.1%(11/155 patients)had a decrease in menstrual volume,including 1 in the POI pre-group(2.6%)2 cases(7.4%)in the early POI group,8 cases(8.9%)in the POI late group,and 5.8%(9/155 cases)patients with amenorrhea,including 3 cases(7.9%)in the POI group and 1 case in the POI group(3.7%),5 cases(5.6%)in the POI late group;4.6%(7/155 cases)patients had premenstrual stage,including 2 cases(5.3%)in the POI pre-group and 5 cases(5.6%)in the POI late group;%(3/155 patients)patients had uterine bleeding,including 1 case(2.6%)in the POI pre-group,2 cases(2.2%)in the POI late group,and 12.9%(20/155 cases)patients with normal menstruation,of which the POI pre-group 4 For example(10.5%),3 patients(11.1%)in the early POI group and 11 patients(12.2%)in the POI late group.There were no significant differences in menstrual periods between the three groups during chemotherapy(P>0.05).(3)Menstruation after 1 year of chemotherapy:40.6%(63/155 patients)had normal menstruation,including 18 cases(47.4%)in the POI group,17 cases(63.0%)in the POI group,and 28 cases(31.1%)in the POI group.38.7%(60/155 patients)in the late menstrual period,including 10 patients(26.3%)in the POI pre-menstrual group(menstrual cycle mostly from 37 days to February),and 4 patients(14.8%)in the early POI group(more menstrual cycle at 37)From February to February,46 patients(51.1%)in the POI late group(menstrual cycle mostly from 37 days to March);14.3%(22/155 patients)developed amenorrhea,including 5 patients(13.2%)in the POI pre-stage.There were 4 cases(14.8%)in the early POI group,13 cases(14.4%)in the POI late group,and 3.9%(6/155 cases)patients with reduced menstrual flow,including 4 cases(10.5%)in the POI pre-group and 1 case in the POI early group.(3.7%),1 case(1.1%)in the POI late group;1.9%(3/155)patients had premenstrual stage,including 1 case(3.7%)in the POI early group and 2 cases(2.2%)in the POI late group;%(1/155 patients)had a uterine leak,which was the pre-POI group(2.6%).The menstrual status of the three groups of patients after chemotherapy was significantly different(P<0.05).(4)Comparison of menstrual conditions in each group of POI:There were significant differences in menstrual periods between menstruation,chemotherapy and 1 year after chemotherapy in the pre-POI group.The menstrual period in the early POI patients was significantly more significant in menstruation,chemotherapy and 1 year after chemotherapy.There was a significant difference in the menstrual period between the patients with advanced POI and menstruation during chemotherapy and 1 year after chemotherapy(P<0.05).3.In the pre-POI group and the early POI group,18.42%(7/38 cases)and 14.81%(4/27 cases)had symptoms of hot flashes and sweating,and 76.92%(70/91 cases)of patients with advanced POI showed moisture.Hot sweating,and 52.6%(47/91 cases)patients with hot flashes ? 3 times/day,the symptom scores were significantly different(P<0.05);other perimenopausal symptom scores were not significantly different(P>0.05).The severity of perimenopausal symptoms in the three groups was moderate(74.07%-89.49%).The Kupperman scale in the POI late group was significantly higher than that in the POI pre-group and POI early group(P<0.05).4.Sex hormone levels(1)After the last chemotherapy:the levels of follicle stimulating hormone(FSH)and luteinizing hormone(LH)in the pre-POI group were 16.025(13.86,18.8)mIU/ml,6.39(1.93,15.1)mIU/ml,and the early group FSH of POI.The LH level was 34.87(29.6,36.7)mIU/ml,21.2(12.5,2.4)mIU/ml,and the FSH and LH levels in the late POI group were 88.37(71.11,105.5)mIU/ml,54.67(42.69,64.63)mIU/The levels of FSH and LH in the late group of ml and POI were significantly higher than those in the pre-POI group and the early POI group(P<0.05).The levels of estradiol(E2),testosterone(T)and progesterone(P)in the pre-POI group were 117.75(33.51,259.7)pmol/L,1.165(0.477,1.65)nmol/L,1.56(1.16,3.04)mol/L,the early group of POI E2,T,P level was 129.2(45.6,258.1)pmol/L,1.23(0.387,1.59)nmol/L,2.36(0.976,2.45)nmol/L,the E2,T,P levels in the late POI group were 27.24(18.35,57.6)pmol/L,0.372(0.162,0.566)nmol/L,0.83(0.546,1.33)nmol/L,the levels of E2,T and P in the POI late group were significantly lower than those in the POI pre-and post-POI groups(P<0.05).There was no significant difference(P>0.05).(2)1 year after chemotherapy:The FSH level in the pre-POI group was 5.55(3.55,6.25)mIU/ml,the early POI group was 6.45(4.77,9.15)mIU/ml,and the POI late group was 6.91(4.2,14.42)mIU/ml.The level of FSH in the late POI group was higher than that in the POI group and the early POI group(P<0.05).The T level in the POI group was 1.145(0.794,1.62)nmol/L,and the early POI group was 1.25(0.987,1.56).In the late group of nmol/L,POI was 0.972(0.613,1.31)nmol/L,and the level of T in the late POI group was lower than that in the pre-POI group and the early POI group(P<0.05).LH and E2 were 1 year after chemotherapy.There were no significant differences in P and PRL levels between the three groups(P>0.05).(3)The level of FSH in the POI pre-treatment group was lower than that in the last chemotherapy,and the E2 level was increased(P<0.05).The level of FSH and LH in the early POI group was lower than that after the last chemotherapy,and the E2 level was increased(P<0.05),the levels of FSH and LH in the late POI group were lower than those in the last chemotherapy,while the levels of T,P and E2 were increased(P<0.05).5.Correlation between FSH level and CTX cumulative dose:A scatter plot of FSH level and CTX cumulative dose was found,and there was a linear correlation between the two variables;FSH level was negatively correlated with CTX cumulative dose after the last chemotherapy(r=-0.1891,P<0.05),1 week after chemotherapy,FSH level was positively correlated with cumulative dose of CTX(r=0.167,P<0.05).6.Prognosis and fertility:The recurrence rate of breast cancer during follow-up was about 5.77%,and the metastasis of the chest wall,contralateral breast,lung and other neighbors occurred.147 patients did not carry cancer.The pregnancy rate was about 6.45%.The rate was about 3.87%,of which the POI late group pregnancy rate(3.33%,3/90 cases)and live birth rate(1.11%,1/90 cases)were the lowest,no significant difference(P>0.05).7.TCM Syndrome:Patients with clinical chemotherapy-derived ovarian dysfunction with normal tongue(81/156 cases,51.92%),pale red tongue(71/156 cases,45.51%),thin white moss(80/156 cases,51.28%),string fine veins(49/156 cases,31.41%)and Shenchimai(55/156 cases,35.26%)were more common;57.9%of patients in the pre-POI group were of liver-kidney yin deficiency syndrome(22/38 cases)6 cases of kidney deficiency and liver stagnation,lease of spleen and kidney yang deficiency,2 cases of heart and kidney disharmony,4 cases of kidney deficiency and blood stasis,3 cases of qi and blood weakness;63%of POI early group belonged to liver and kidney yin deficiency syndrome(17/27 2 cases,2 cases of kidney deficiency and liver stagnation,2 cases of heart and kidney disharmony,3 cases of kidney deficiency and blood stasis;49.5%of POI late group belonged to liver and kidney yin deficiency type syndrome(45/91 cases),kidney deficiency liver depression 12 cases,spleen and kidney 10 cases of yang deficiency,8 cases of heart and kidney disharmony,11 cases of kidney deficiency and blood stasis,5 cases of qi and blood weakness;TCM syndromes of chemotherapy-derived ovarian function impairment were more common in liver-kidney yin deficiency syndrome(84/156 cases,53.8)%)There was no significant difference in the distribution of TCM syndromes between the three groups(P>0.05).Conclusions1.The level of CTX chemotherapy-derived ovarian function was evaluated by serum FSH as the standard after the last chemotherapy.There was no significant correlation between the degree of injury and the age of onset.The peak age of onset of chemotherapy-induced ovarian function was 35-39 years old.2.CTX chemotherapy causes breast cancer patients with different degrees of menstrual disorders during chemotherapy,more common in the late menstrual period,followed by amenorrhea,decreased menstruation,early menstruation;with time,menstrual disorders can be improved to some extent,improve It is related to the degree of ovarian function damage.After 1 year of chemotherapy,more than half of the patients in the POI late group(65.56%)can not return to normal menstruation,which is characterized by late menstruation or even amenorrhea.3.Accompanying peri-menopausal symptoms:chemotherapy-derived ovarian premature aging patients with moderate menopausal symptoms were moderately moderate;POI late group KI symptom scores were higher,peri-menopausal-related symptoms than POI pre-group,early POI The group was severe,and the symptoms of hot flashes were more prominent.4.CTX chemotherapy can lead to increased levels of FSH and LH,and decreased levels of E2,T and P.The degree of POI in the late group is significantly higher than that in the pre-POI group and the early group.The level of sex hormones can be restored to some extent after chemotherapy,and the FSH level is lower than the last time.At the end of chemotherapy,there was a significant decrease,but the average level of FSH in the late POI group was still higher than that in the other two groups.The E2 level was significantly higher than that at the end of the last chemotherapy.Chemotherapy with CTX will cause different damage to ovarian function in patients with breast cancer characterized with menstrual disorders,symptoms related to perimenopause,increased level of FSH and decreased level of E2 and T.The laws of pathogenesis is deficiency of kidney essence,yin and blood,as well as liver depression and blood stasis.The most common characteristic of TCM symptoms was deficiency of liver and kidney.We also found that changes of the levels of sexual hormones could be reserved 1 year after the last chemotherapy,which indicated that impaired ovarian function could be self-repaired to some extent which was related to the accumulated dosage of CTX and degree of ovarian damage.Observing the clinical symptoms and menses,as well as detecting the levels of sexual hormones not only make sense in evaluating the degree of ovarian damage,but also provide evidences for the further study of ovarian toxicity caused by chemotherapy. |
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