Progress in treatment of premature ovarian failure using Chinese and western medicine

Wen-Ming Cao,Shu-Ling Zhang,Yan-Ling Li,Yu Na,Xin-Liang He

1Shandong Changle People's Hospital, Shandong, China. 2Shandong Provincial Third Hospital, Shandong, China.3Shandong Dezhou Hospital of Traditional Chinese Medicine,Shandong,China.

Abstract Premature ovarian failure (POF) refers to ovarian failure in patients before the age of 40, which is manifested by a series of symptoms such as hot flashes, hyperhidrosis, facial flushing, low sexual desire, amenorrhea, etc.Gynecological endocrine tests show that estrogen level of patients decreases while follicle stimulating hormone level increases, affecting pregnancy of women of childbearing age and seriously causing changes in the quality of life of patients. The causes of POF are complex with poor therapeutic effect, which seriously endangers the physical and mental health of patients.This paper summarized the a general description of Chinese medicine (CM)and Western medicine (WM) treating POF from the aspects of clinical application according to the existing literature. Although WM can significantly contribute to the treatment of POF, the side effects are serious by long-term application. CM has unique advantages, including reduced adverse reactions and higher patient compliance. It may also fill in the shortcomings of WM in the intermittent period treatment of POF. The combination of Chinese and western medicine has proven to become an important direction for POF treatment.

Keywords:Premature ovarian failure,Etiology,Research progress,Chinese medicine,Western medicine

Introduction

Premature ovarian failure (POF) is the cessation of ovarian function before 40 years of age, also recognized as premature ovarian dysfunction or premature ovarian insufficiency. POF is defined as follows: ①age ＜40 years old; (2) follicle stimulating hormone(FSH)＞40mlU/ml,lasting for more than two times, and the interval between each examination should be ≥1 month; ③amenorrhea time ≥6 months;the patient did not use sex hormone drugs such as estrogen and progesterone and corticosteroids within 1 month. However, amenorrhea caused by pregnancy,polycystic ovary syndrome, mental stimulation and environmental changes must be excluded clinically.The incidence rate of POF in China is 1%-3.8%,which poses a serious threat to the health of patients [1].From analysis based on chromosome karyotype, poor ovarian reserve, premature ovarian failure and early menopause are family genetic diseases, which are related to autosomal transmission. Some scholars believe that POF is due to X-linked genetic diseases.This paper summarized the a general description of pathogenesis of POF, Chinese medicine (CM) and Western medicine (WM) treatment for POF from the aspects of clinical application.

Pathogenesis

X chromosome abnormality and autosomal related genes

POF is a group of X-linked genetic diseases.Chromosome translocation, recombination and monomer changes of chromosomes will lead to the occurrence and development of POF, seriously affect the therapeutic effect and have poor prognosis[2].Two X chromosomes with normal structure are the premise for women to give birth. Bone morphogenetic protein 15 gene is vital to the early proliferation and development of follicles. This gene can promote the growth of dominant follicles and is a candidate gene for POF [3]. Mutation of gonadotropins and their receptors can lead to gonadotropin dysfunction and POF. The mutation of ovarian stimulating hormone receptor gene may be the molecular pathological basis of premature ovarian failure.This gene is an autosomal related gene and is positively correlated with the symptoms of POF.

Autoimmune factors

As far as current clinical research is concerned,there is no final conclusion about what the degree of POF can be caused by autoimmune damage in patients with POF. It is reported that the patients produce relevant antibodies in the body due to hyperautoimmune function. Antibodies may recognize and damage certain ovarian components.

Immune dysfunction. The study showed that the abnormal structure and function of immune cells could damage the ovary. When the ovary ovulates, the cells of ovarian tissue can enter the blood circulation to produce anti-ovarian autoantibodies (AOA). The positive rate of AOA antibody accounts for 60%-70%of patients with POF. Irvine et al. [4] reported that patients with POF were immunologically related to non-specific Addison's disease.Anti-ovarian antibodies not only exist in the blood circulation of patients with POF, but also directly act on the ovary, causing follicular atresia and follicular underdevelopment,lowering estrogen level and increasing gonadotropin level in the body,thus leading to ovarian failure.

Anti-zona pellucida antibody.Advanced fluorescence immunoassay technology can be used to detect anti-zona pellucida antibodies in patients' blood. Zona pellucida rupture and reabsorption can occur repeatedly in patients with POF, which can make the body of women of childbearing age in a special sensitive stage of antigen and antibody stimulation when ovulating, causing patients to tonify the kidney clinically. The occurrence of autoimmune ovarian inflammation is closely related to the response of ZP3 antibody and T lymphocyte in vivo.Once this antibody and transparent antibody are detected, intervention must be carried out.

Anticardiolipin antibodies.Anticardiolipin antibodies are also called autoimmune antibodies clinically. It is closely related to venous thrombosis disease, Sjogren's syndrome, immune diseases, cardiovascular diseases,gynecological infertility and habitual abortion.Anticardiolipin antibodies are closely related to POF.

Combination with other immune diseases.One fifth of POF patients were complicated with autoimmune diseases. Ishizuka et al. [5] reported that among patients with normal karyotype, the amenorrhea time of patients with negative antinuclear antibody is significantly delayed compared with that of patients with positive antinuclear antibody. Antinuclear antibody may be one of the immunological mechanisms of ovarian dysfunction and POF.

Iatrogenic factors

Radiotherapy, chemotherapy and drug damage.Radiotherapy can destroy ovarian cortex, leading to irregular menstruation and even amenorrhea. Some patients suffered from dysphoria, insomnia, anxiety and depression can lead to poor ovarian reserve and premature ovarian failure. Large doses of radiation exceeding 8.0 Gy can cause ovarian function damage and lead to irreversible ovarian failure. Large doses of chemotherapy drugs such as methotrexate,gemcitabine,epidorubicin, fluorouracil, paclitaxel, cisplatin,cyclophosphamide, etc. can also lead to ovarian dysfunction. Long-term administration of traditional Chinese medicines such as Tripterygium wilfordii can also cause premature ovarian

Operation. All pelvic and abdominal operations on tissues around the ovary may affect ovarian blood supply and cause premature ovarian failure. All open or laparoscopic ovarian tumor removal and ovariectomy can affect ovarian function. In recent years, a large number of reports showed that Laparoscopic electrocautery could seriously affect ovarian function. It has been reported that during laparoscopic surgery, absorbable suture is used to reconstruct the ovary as far as possible, instead of electrocoagulation to stop bleeding.No matter unipolar or bipolar electrocoagulation, it will cause damage to the ovary. In case of electrocoagulation, cold water is used to continuously flush during electrocoagulation as far as possible during the operation,so as to reduce the indicated temperature of the ovary and minimize the damage to the ovary.

Uterine artery embolization.Uterine artery embolization is now widely used in the treatment of gynecological tumor diseases.Regardless of the benign and malignant nature of the tumor, a large number of reports on uterine artery embolization can be seen in the data. In patients with abortion and postpartum hemorrhage,although some patients retained the uterus through uterine artery embolization, the probability of POF in such patients was significantly increased in future follow-up observation.

Congenital enzyme deficiency, infection and environmental factors

Deficiency of galactose-1-phosphate uridyltransferase in erythrocytes can not only damage embryonic follicle cells,but also damage ovarian parenchyma, change the biological activity of gonadotropins, reduce the number of primordial follicles in ovary, cause premature depletion of follicles and POF.

Ovary itself has anti-infection ability, but severe viral mumps, ureaplasma urealyticum and chlamydia trachomatis infection, gonococcus infection, pelvic abscess and tuberculosis, some sexually transmitted diseases and other gynecological diseases can lead to partial or complete loss of ovarian function, thus causing ovarian damage. Environmental pollution and air pollution can endanger human reproductive function and also cause embryonic dysplasia.

Abnormal hormone levels and follicular reserve and depletion

Abnormal gonadotropin receptor and estrogen receptor.POF is caused by homozygous mutation of the follicle stimulating hormone receptor (FSHR) or heterozygous mutation of the FSHR.Female fertility is also related to luteinizing hormone (LH) receptor gene mutation and abnormal molecular structure of luteinizing hormone. In addition, abnormal expression of estrogen receptor polymorphism and abnormal estrogen receptor also cause irregular menstruation,POF and early amenorrhea.

Inhibin abnormality.Abnormal function and structure of inhibitin caused by mutation of inhibitin gene can selectively inhibit the secretion of follicle stimulating hormone and also lead to POF.

Psychological factors

Long-term malignant bad mood can disturb hypothalamus-pituitary-ovary axis, causing abnormal menstruation and even amenorrhea. Melancholy,sadness, fear, loss, nervousness and anxiety can affect ovarian reserve function and cause POF.

Treatment of POF from the view of WM

The treatment of POF in modern medicine is mainly hormone replacement therapy.In addition,genetherapy,immunotherapy,auxiliary egg donation therapy,mental support therapy and the prevention of damage factors all have a certain curative effect on POF. Recent experimental studies have shown that stem cell transplantation has a definite therapeutic effect on POF model animals, which can provide a basis for clinical treatment of POF patients.

Hormone replacement therapy(HRT)

HRT is the first choice for the treatment of POF,which can relieve a series of symptoms caused by sex hormone deficiency in POF patients, such as hot flashes, emotional agitation, sore waist and knees,dizziness and tinnitus, vaginal dryness and so on. The clinical application of HRT is mainly divided into the single use of estrogen and the combined use of estrogen and progesterone. Teng Xiuxiang et al.reported [6] 62 patients with POF were treated with estrogen plus progesterone for 6 months, and the total effective rate was 74.19%.However,it should be noted that long-term clinical use of HRT, could cause endometrial thickening, endometrial abnormal bleeding,and even endometrial cancer or breast cancer.Bilateral uterine appendages and breast color ultrasound should be monitored regularly. It has been reported that the number of follicles in patients with POF treated with HRT decreased rather than increased,and the clinical pregnancy rate and menstrual cycle rate decreased significantly.

Genetherapy

With the improvement of gene database, gene therapy has gradually become a new method of treatment,which refers to the artificial introduction of exogenous gene fragments into the gene sequence of target tissues or target cells[7] to inhibit the expression of defective genes to correct or compensate defective genes, so as to achieve the purpose of treating diseases.Experimental studies [7] have shown that bilateral injection of adenovirus vector carrying FSHR gene into the ovaries of POF mice with FSHR gene can decrease the levels of FSH and LH in blood and increase the level of estradiol in mice, thus improving the physiological function of ovaries and restoring the function of ovaries secreting estrogen. But gene therapy has not been used to treat POF in clinical practice,most of them are used as pregnancy guidance.Gene testing is performed on high-risk people with family genetic history to determine whether to get pregnant as early as possible to avoid the great mental stress caused by infertility.

Immunotherapy

There is no unified treatment standard for immunotherapy.Glucocorticoid can be used in patients with positive autoimmune antibodies in blood. The commonly used drugs are prednisone or dexamethasone, the mechanism may be related to reduce the level of CD4+T cells in blood and decrease the level of autoimmune antibodies in patients with POF; but the curative effect is uncertain. Aspirin can be used in patients with positive anticardiolipin antibodies in blood. The study by Gao Yujuan [8]found that soybean isoflavone could effectively inhibit anti-Zona pellucida antibodies in mice by improving the immune function to restore ovarian physiological function.

Stem cell transplantation therapy

Stem cells are a kind of primitive stem cells with multiple differentiation potential. Boregowda et al. [9]found that mesenchymal stem cells could differentiate into oocytes in the ovary of POF animal model,increase the number of follicles in the body,restore the level of estrogen in the body, and achieve the purpose of treating POF. The immunogenicity of stem cells with multi-directional differentiation potential is also very low, and almost no rejection occurs in the human body, so stem cell transplantation is a safe and effective treatment, which is worthy of further clinical research.

Auxiliary egg donation and embryo transfer(IVF-ET)therapy

Egg donation and IVF-ET therapy are the most effective treatments for POF patients with fertility requirements. Wang Ting [10] et al. used the egg donation and IVF-ET therapy to make the pregnancy of POF patients successful. In contemporary society,egg donation is restricted by ethics and relevant laws,and the source of eggs needs to be solved urgently,which limits the further development of this therapy.

Psychological support therapy

POF patients have a long course of disease. With the further development of the disease, the endocrine system is maladjusted, which affects the mood of patients lead to produce varying degrees of sadness,depression,tension or anxiety,while negative emotions can aggravate the damage of ovarian function and form a vicious circle.The study by Liu Jing [11] found that the effect of simple HRT treatment was not as obvious as that of HRT combined with psychological counseling,and patiently communicating with patients,constantly appeasing the mood of patients,psychological counseling to patients can promote the improvement of the condition of POF patients.

CM in treatment of POF

The application of CM in China has a long history, its theoretical system is complete, and the application forms are various, and it is widely used in prevention,treatment and diagnosis of diseases. CM is not a hormone, but it can improve the endocrine level of the body,play a hormone-like role,strengthen the response between hormones and receptors, and improve ovarian function.

Chinese medicinal herbs(CMHs)treatment

Gao Hui[12] et al treated POF 60 cases with Bushen Tiaochong recipe or hormone replacement therapy for 3 months; the total effective rate in the Bushen Tiaochong recipe group and the hormone replacement therapy group were 93.3% and 90% respectively. In terms of side effects, there were no adverse reactions in the Bushen Tiaochong recipe group, while the adverse reactions in the hormone replacement therapy group were aggravated with the increase of treatment time. The long-term effect of the Bushen Tiaochong recipe group was significantly better than that of the hormone group. Li Dajian et al [13] used Bushen Tiaojing decoction combined with auricular point pressing to treat POF patients; the effective rate was 84.85%. Bushen Tiaojing decoction combined with auricular point pressing could promote ovarian function, reconstruct the response between ovary and pituitary, enhance its sensitivity and responsiveness,and enhance the feedback and negative feedback function of hypothalamus-pituitary-ovarian gland axis.Tang Haixia, et al [14] used Yishen Tiaochong decoction combined with moxibustion to treat POF;Guanyuan, uterus, Zusanli and Sanyinjiao acupoints were selected;The result showed that the level of FSH and LH were decreased and the level of E2 was increased, and the total effective rate was 82.5%;compared with the control group (hormone replacement therapy), the curative effect was not significantly different, but the improvement of clinical symptoms was significantly better than that of patients treated with hormone.Wu Zhaoxi et al. [15]treated 33 patients POF with oral Yishen Huoxue decoction and acupoint massage, while 26 patients in the control group were treated with hormone replacement therapy;the results showed that the clinical symptoms and serum hormone levels were improved in both the treatment group and the control group; however,compared with the control group, the improvement of serum hormone E2 level in the treatment group was the most significant. Fang Qingxia et al.[16] treated POF patients with CM combined with catgut embedding,and the control group was treated with hormone sequential therapy;the results showed that the effective rates of the two groups were 89.47% and 76.32%respectively.At the same time,the treatment group was superior to the control group in the changes of clinical symptom scores,serum hormone (FSH, LH, E2)levels and safety.

Acupuncture treatment

Acupuncture is a therapeutic technique that adjusts the functional state of the body by stimulating meridians and acupoints. The therapeutic effect of acupuncture is related to the site of action,the intensity of stimulation,the nature of induction and so on. Acupuncture has a long history in the treatment of gynecological diseases,menstrual diseases and similar diseases.

Yang Xiaohong [17] treated 60 POF cases; thirty cases in the treatment group were treated with acupuncture and 30 cases in the control group were treated with artificial cycle therapy; the effective rates of the two groups were 90% and 56.67% respectively,and compared with the control group, the treatment group was effective in reducing serum follicle stimulating hormone and increasing the level of estradiol. Feng Xiaojun [18] treated 32 POF patients with electroacupuncture combined with pelvic floor muscle massage;the results showed that the symptoms of peri-menopausal period and the level of serum hormone were significantly improved.Li Shuxiang[19]treated 32 POF patients with acupuncture combined with Shenque ginger-separated moxibustion on Xuehai,Sanyinjiao, Guanyuan acupoints and ovary; a total effective rate was 90.6%. Tian Haiyan, et al [20]applied electroacupuncture combined with heat-sensitive moxibustion to treat 60 cases with POF,once a day for 6 months; a total effective rate was 93.3%and the patients' clinical symptoms such as sore waist and knees, palpitation, irritability,depression has been significantly improved.The study by Li Ning[21]showed that the total effective rate of acupuncture combined ear pressure treating POF was 90.0%, and it could promote ovulation without any adverse reactions.

Catgut embedding therapy

Catgut embedding therapy is a perfect display of the theory of"deep acceptance and long stay".In the study of the clinical efficacy of acupoint catgut embedding in the treatment POF [22], 30 POF patients were treated with catgut embedding therapy and hormone replacement therapy respectively. After 3 months of treatment, the effective rates of the two groups were 90.00%and 86.67%respectively,but after 3 months of follow-up, the effective rates of the two groups were 86.67% and 43.33%, respectively. It can be seen that the long-term effect of the acupoint catgut embedding group is more longer when the therapeutic effect is almost the same.At the same time,the improvement of clinical symptom score, serum hormone level and endometrial thickness in the acupoint catgut embedding group was better than that in the hormone replacement therapy group.

Auricular point therapy

Auricular points are commonly used for the treatment of premature ovarian failure,such as internal secretion,pelvic cavity,kidney,subcortex,liver and so on.Cheng Xijian [23] pointed out that auricular point pressing bean combined with Shuangbai heat compress could promote local blood flow, the recovery of ovarian function and ovulation after operation; at the same time, the clinical symptoms of the patients have been greatly improved.

Integrated CM and WM treatment

Traditional Chinese medicine has advantages in the treatment of POF,but it also has the deficiency of slow curative effect, and the combination of CM and WM can learn from each other and better meet the needs of patients. In the study by Xu Xun [24] of combination of CM and WM in the treatment of POF, the treatment group was treated with acupuncture, CMHs, and hormone, while the control group was treated with hormone only; results showed the changes of serum hormones and the improvement of clinical symptoms in the treatment group were better than those in the control group, and the effective rate was higher than that in the control group. This study suggested that acupuncture and CMHs could regulate the endocrine level of the body, especially in improving the responsiveness of the ovary and the content of ovarian sex hormone receptors. Lu Dongfang [25]treated POF patients with CMHs for tonifying kidney, nourishing blood and promoting blood circulation combined with WM (estradiol valerate, medroxyprogesterone) in the treatment group, while the control group was treated with WM; results showed it was superior in the treatment group than that of the control group in improving symptoms, improving quality of life,increasing E2 level and regular menstrual cycle. In the study by Li Weidong[26],catgut embedding combined with artificial cycle therapy was used in the treatment group, while the patients of control group was only treated with artificial cycle therapy;results showed the clinical symptoms and serum hormone levels of the two groups were significantly been improved before and after treatment, but the treatment group was better than the control group.

Experimental study for CM on treating POF

Han Bo [27] established the POF rat model by cyclophosphamide and treated with Kangshuai Funest

granule; the results suggested that Kangshuai Funest granule could regulate the sex hormone of POF rats,increase the level of E2 and decrease the level of FSH,which was better than that of WM group. The ovarian tissue of POF rats was examined;it was found that the growth of follicles and the number of luteal cells were increased,which were close to normal.Luo Xiaoguang[28]et al. treated POF patients with catgut embedding and CMHs, and the results showed that endometrium thickened, glandular blood circulation was abundant,and ovarian function was enhanced, indicating that acupoint catgut embedding and CMHs could improve ovarian reserve function and effectively prevent the decline of ovarian reserve function. Sun Yongzhong[29] et al. gave low, middle and high doses of Zishen Yichong Kangshuai decoction in three groups of POF rats; the results showed that Zishen Yichong Kangshuai decoction could shorten the time of interestrus, prolong the time of estrus and regular estrus cycle, and increase the content of E2 in peripheral blood, the weight of uterus and ovary, the number of growing follicles and the number of mature follicles. It showed that Zishen Yichong Kangshuai decoction has obvious therapeutic effect on POF rats,and the mechanism is the estrogenic effect of CMHs,which could improve ovarian function through hypothalamus-pituitary-ovary axis or other action ways.

Summary

The increasing incidence of POF has seriously affected women's physical and mental health. Although WM can significantly contribute to the treatment of POF,the side effects are serious by long-term application.CM has unique advantages, including reduced adverse reactions and higher patient compliance. It may also fill in the shortcomings of WM in the intermittent period treatment of POF. The combination of Chinese and western medicine has proven to become an important direction for POF treatment.