An update on primary ovarian insufficiency

Primary ovarian insufficiency(POI) occurs in about 1% of female population under the age of 40,leading to reproductive problems,an earlier encounter with menopausal symptoms,and complicated diseases.There are three presumable mechanisms involved in the development of POI,namely apoptosis acceleration,follicular maturation blocking and premature follicle activation,through the following studied causes:(i) chromosomal abnormalities or gene mutations:mostly involve X chromosome,such as FMR1 premutation;more and more potentially causal genes have been screened recently;(ii) metabolic disorders such as classic galactosaemia and 17-OH deficiency;(iii) autoimmune mediated ovarian damage:observed alone or with some certain autoimmune disorders and syndromes;but the specificity and sensitivity of antibodies towards ovary are still questionable;(iv) iatrogenic:radiotherapy or chemotherapy used in cancer treatment,as well as pelvic surgery with potential threat to ovaries' blood supply can directly damage ovarian function;(v) virus infection such as HIV and mumps;(vi) toxins and other environmental/lifestyle factors:cigarette smoking,toxins(e.g.,4-vinylcyclohexene diepoxide),and other environmental factors are associated with the development of POI.The etiology of a majority of POI cases is not identified,and is believed to be multifactorial.Strategies to POI include hormone replacement and infertility treatment.Assisted conception with donated oocytes has been proven to achieve pregnancy in POI women.Embryo cryopreservation,ovarian tissue cryopreservation and oocyte cryopreservation have been used to preserve ovarian reserve in women undergoing cancer treatments.

Advances in biomaterials and regenerative medicine for primary ovarian insufficiency therapy

Primary ovarian insufficiency(POI)is an ovarian dysfunction that affects more than 1%of women and is characterized by hormone imbalances that afflict women before the age of 40.The typical perimenopausal symptoms result from abnormal levels of sex hormones,especially estrogen.The most prevalent treatment is hormone replacement therapy(HRT),which can relieve symptoms and improve quality of life.However,HRT cannot restore ovarian functions,including secretion,ovulation,and fertility.Recently,as part of a developing field of regenerative medicine,stem cell therapy has been proposed for the treatment of POI.Thus,we recapitulate the literature focusing on the use of stem cells and biomaterials for POI treatment,and sum up the underlying mechanisms of action.A thorough understanding of the work already done can aid in the development of guidelines for future translational applications and clinical trials that aim to cure POI by using regenerative medicine and biomedical engineering strategies.

Analysis of Chinese women with primary ovarian insufficiency by high resolution array-comparative genomic hybridization

Background Primary ovarian insufficiency （POI） is defined as a primary ovarian defect characterized by absent menarche （primary amenorrhea） or premature depletion of ovarian follicles before the age of 40 years. The etiology of primary ovarian insufficiency in human female patients is still unclear. The purpose of this study is to investigate the potential genetic causes in primary amenorrhea patients by high resolution array based comparative genomic hybridization （array-CGH） analysis. Methods Following the standard karyotyping analysis, genomic DNA from whole blood of 15 primary amenorrhea patients and 15 normal control women was hybridized with Affymetrix cytogenetic 2.7M arrays following the standard protocol. Copy number variations identified by array-CGH were confirmed by real time polymerase chain reaction.

Roles of Meiotic Defects in Pathogenesis of Primary Ovarian Insufficiency

A matured oocyte has experienced three critical division stages: (1) proliferation in early fetal stage, (2) meiotic arrest at diplotene of prophase I, and (3) meiotic resumption and extrusion of the first polar body. The abnormalities of these stages are associated closely with female reproduction problems including primary ovarian insufficiency (POI), the pathogenic mechanisms of which consist of insufficient initial follicle number, accelerated follicle loss, and arrest of follicle development. Recently, many meiotic associated genetic factors were identified to be mutated in POI patients and mouse models, revealing the association between meiosis and ovarian reserve. In this review, we provide an overview of the genetic factors involved in meiotic prophase I and their pathogenic mechanisms in POI.

Analysis of the Fragile X Mental Retardation 1 Premutation in Han Chinese Women Presenting with Primary Ovarian Insufficiency

Background: The aim of this study is to investigate the prevalence of the fragile X mental retardation 1(FMR1) gene premutation in Han Chinese women with primary ovarian insufficiency(POI) using a rapid and cost-effective method. Methods: A total of 153 Han Chinese women with sporadic POI were systematically analyzed for trinucleotide repeats within the FMR1 gene. We employed an improved strategy to screen for cytosine-guanine-guanine repeats in the 5’ untranslated region of the FMR1 gene. Before using the previously reported Fragil Ease polymerase chain reaction(PCR) method for premutation identification, we developed a new cost-effective PCR-based method to exclude most of the normal allele carriers during the initial screening stage. Results: In our initial screening, 62.1% of women with POI were found to carry heterozygous normal alleles of FMR1, which were recognized by our sensitive and cost-effective method. The remaining women were further screened for the presence of the FMR1 premutation. We identified a Han Chinese woman with a premutation allele of FMR1 out of 153 sporadic POI women(0.7%). Conclusions: The frequent FMR1 premutation in Caucasian individuals with POI may not be a common genetic cause of sporadic POI in the Han Chinese population.

Efficiency and safety of acupuncture for women with premature ovarian insufficiency:study protocol for a randomized controlled trial

Acupuncture has been widely used as an alternative and complementary therapy for premature ovarian insufficiency(POI)in China.However,research to date has not shown that acupuncture is effective for POI compared with hormone replacement therapy(HRT).We will conduct a randomized,controlled,and outcome assessor-blind trial to evaluate the efficacy and safety of acupuncture on POI.Seventy-six patients with POI will be randomly assigned to two groups.The treatment group will receive twenty-eight one-hour sessions of acupuncture treatments,and the control group will receive 12-week HRT.The whole study will consist of a 12-week treatment plan and a 12-week follow-up session.The primary outcome is measured by changes in serum anti-Müllerian hormone and follicle-stimulating hormone(FSH)levels at weeks 12 and 24.Secondary outcome measures include estradiol,luteinizing hormone(LH),LH/FSH ratio,Kupperman index,and menstrual condition.This trial is expected to clarify whether or not acupuncture is effective and safe for POI compared with HRT.

Efficacy of Bushen Culuan decoction(补肾促卵方)on ovarian follicle and follicular granulosa cells in mice with premature ovarian insufficiency induced by tripterygium wilfordii polyglycoside

OBJECTIVE:To investigate the protective efficacy of Bushen Culuan decoction补肾促卵方,BCD)on ovarian follicle and follicular granulosa cells in mice with premature ovarian insufficiency(POI)induced by tripterygium wilfordii polyglycoside,and to study the potential mechanism underlying the action.METHODS:Eighty female Balb/c mice were randomly divided into 4 groups(n=20 each):blank group,model group,Bushen Culuan decoction intervening group(BCD group)and estradiol valerate intervening group(EV group).In the first 14 model establishing d,mice in model group,BCD group and EV group were under Tripterygium wilfordii polyglycoside(TWP)gavage to establish POI models.In the 14-day therapeutic stage,mice in BCD group were taken BCD 18.35 mg·kg^(-1)·d^(-1),mice in EV group were taken EV solution 0.15 mg·kg^(-1)·d^(-1),while mice in blank group and model group were taken normal saline.When the mice accomplished therapy,whole blood was collected for serum hormone including follicle stimulating hormone(FSH),luteal hormone(LH),estradiol(E2),antimullerian hormone(AMH)levels and vascular endothelial growth factor(VEGF),bone morphogenetic protein-7(BMP-7)measurement.Ovarian tissues were harvested for morphologic observation,follicle counting,ovarian follicular graulosa cell apoptosis test and testing BMP-7 and caspase-3 expressions.RESULTS:The body weights of the mice kept growing stably in the process expect in TWP intervening stage.Compared with model group,BCD group had significantly higher ovarian index,serum E_(2),AMH,VEGF,BMP-7 levels and significantly lower FSH level(P<0.05).Meanwhile the VEGF level in BCD group was higher than in EV group(P<0.05).Compared with model group,the histopathological damage and GCs apoptosis were mitigated;developing follicle counting,BMP-7 expression were up-regulated,and caspase-3 expression was downregulated in BCD groups(P<0.05).CONCLUSION:BCD treatment could attenuate pathological process in POI ovaries,suppress GC apoptosis,probably through promoting BMP-7 expression and following inhibiting caspase-3 activation.

Natural products for treatment of premature ovarian failure:a narrative review

Premature ovarian failure(POF) is a female reproductive system disease caused by many factors and systems,which has seriously affected the quality of life of women of childbearing age.Clinically,the disease is difficult to treat while its incidence rate shows an increasing trend.In recent years,natural products used as multi-pathway,multi-target and efficient drugs,have become the focus of many research and clinical studies in China and abroad,and the effect of phytochemicals derived from edible plants and Chinese medicine herbs on POF were investigated in several papers.Using "premature ovarian failure" or "ovary" and related natural products as keywords,we retrieved and reviewed research articles from China National Knowledge Infrastructure Database,Wanfang,Pub Med,Web of Science and other literature databases.Up to October,2021,natural compounds with prophylactic or interference inhibition effects on POF mainly included flavonoids,polysaccharides,saponins,and polyphenols.Their effect on POF and ovarian function was closely related to their antioxidant,antiapoptotic,antiaging,immunoregulatory and estrogenlike activities.

Apoptotic mechanism of premature ovarian failure and rescue effect of Traditional Chinese Medicine: a review

Social and environmental factors render premature ovarian failure(POF) as a major cause of decline or loss of female fertility. The natural pregnancy rate of patients with POF is only 5%-10%. Follicular atresia is the main factor in the pathogenesis of POF.Due to the unique ovarian physiological environment and follicular developmental processes, the apoptosis of ovarian granulosa cells and oocytes together cause follicular atresia, which involves the apoptosis-related internal and external pathways.Furthermore, during POF, apoptosis and oxidative stress forms a "vicious circle", which involves a variety of changes between the molecules. The existing pharmaceutical preparations such as gonadal hormones are the basic methods for the treatment of POF, and the curative effect was affirmative;however, it was ineffective after withdrawn, while the long-term application led to adverse reactions. Traditional Chinese Medicine(TCM) has a history of treating gynecological diseases and infertility and has gained increasing attention. Studies have shown that compounds isolated from herbal medicine exerted a positive effect on follicular atresia caused by cell apoptosis that also improved the POF. The present study reviewed the mechanisms underlying the apoptosis in POF and elaborated the internal mechanism of TCM in the treatment of the condition.

Effect of Er-Xian decoction(二仙汤) on autoimmune premature ovarian failure in mice

OBJECTIVE:To investigate the therapeutic effect of Er-Xian decoction(二仙汤,EXD)on the autoimmune premature ovarian failure(POF)in mice,and its regulatory mechanisms.METHODS:Female BALB mice were treated with a single intraperitoneal injection of zona pellucida 3(ZP3).One week later,mice received low(5 g/kg),moderate(10 g/kg)and high(20 g/kg)doses of EXD by gastrogavage once daily for 90 d.Premarin(0.03 mg/kg)served as the positive control group.Serum levels of estradiol(E2),follicle stimulating hormone(FSH)and luteinizing hormone(LH)were measured by enzyme-linked immunosorbent assay,lymphocyte subtypes were analyzed,and follicular structure differences were observed by hematoxylin andeosin staining.The main mechanisms of POF was investigated by immunohistochemical analysis.RESULTS:Serum E2 levels in POF model mice were decreased,whereas FSH and LH levels were dramatically increased.Serum levels of LH and FSH were reduced in POF model mice treated with EXD(moderate and high doses)and premarin,while serum level of E2 were increased after POF model mice had been treated with EXD and premarin.The CD3+T,CD4+T,CD4+T/CD8+T ratio of mice in the positive control group and high and medium dose groups of EXD increased(P<0.05),and the number of CD8+T cells decreased significantly(P<0.05)when compared with the model group.Bone morphogenetic protein 15(BMP15)and Akt were repressed in autoimmune POF model mice,whereas high expression was observed in control mice and those treated with EXD(moderate and high doses)and premarin.CONCLUSION:EXD is effective in treating ZP3-induced POF in mice and increased expression of BMP-15,and Akt is represented in the mechanism accounting for this therapeutic effect.

Efficacy of Bushenjianpi prescription on autoimmune premature ovarian failure in mice

OBJECTIVE: To assess the efficacy of Bushenjianpi prescription(BSJPP), a formula from Traditional Chinese Medicine, on a mouse model of autoimmune premature ovarian failure(POF) induced by mouse zona pellucida(ZP3) and to investigate the mechanisms underlying the action.METHODS: After randomization, POF was induced in the model mice by immunization with ZP3. One week later, mice received low(8.1 mg/kg), moderate(16.2 mg/kg) and high(32.4 mg/kg) doses of BSJPP by gastrogavage once daily for 90 days. Premarin(0.03 mg/kg) served as the positive group. Serum samples were collected 1 week after the last dose and stored at-20 ℃ for analysis. After cervical dislocation, the uterus and ovaries were collected aseptically for evaluation by histological assessment, scanning electron microscopy, immunohistochemical staining, and Western blot and reverse transcription-polymerase chain reaction analyses.RESULTS: Serum E2 levels in POF model mice were decreased, whereas follicle-stimulating hormone(FSH) and luteinizing hormone(LH) levels were dramatically increased. Serum levels of E2,LH and FSH were reduced in POF model mice treated with BSJPP(moderate and high doses) and premarin. Anti-bone morphogenetic protein 15(BMP-15) and connexin 43(Cx43) were repressed in autoimmune POF model mice, whereas high expression was observed in control mice and those treated with BSJPP(moderate and high doses)and premarin.CONCLUSION: BSJPP is effective in treating ZP3-induced POF in mice and the increase in the expression of BMP-15 and Cx43 may be implicated in the mechanism underpinning the action.