Research on the aetiology and treatment of premature ovarian insufficiency

Wang Kai-Li,Zhang Yi-Li,＊Xi Yuan Hospital,China Academy of Chinese Medical Sciences,Beijing 00700,China.Beijing University of Chinese Medicine,Beijing 0009,China.

Abstract Premature ovarian insufficiency,as a complex gynaecological disease,seriously threatens the physical and mental health of women of childbearing age.The main reasons for its pathogenesis are summarized.As a complex gynaecological disease,premature ovarian insufficiency seriously threatens the physical and mental health of women of childbearing age.The causes of the disease mainly include genetic defects,autoimmune disorders,radiotherapy and chemotherapy,infection,surgery,adverse environmental exposures and other factors.In more than half of cases,the cause remains unclear.In the clinic,hormone replacement therapy is used mainly to relieve the symptoms of oestrogen deficiency.This article reviews the research progress on the causes and treatment of premature ovarian insufficiency in recent years.

Keywords:Premature ovarian insufficiency,Cause of disease,Treatment research

Background

Previously,premature ovarian insufficiency (POI) was called premature ovarian failure (POF) or primary ovarian insufficiency.The American Society of Reproductive Medicine first proposed the concept of primary ovarian insufficiency in 2008.With the continuous progress of clinical trial research,a more comprehensive understanding of the aetiology and pathogenesis of this disease has been developed.In 2016,it was renamed POI.Currently,POI is the term used in clinical practice.According to the ESHRE guidelines,POI in women refers to ovarian dysfunction before the age of 40 years and manifests mainly as menstrual abnormalities (amenorrhea,oligomenorrhea,or frequent menstruation),elevated gonadotropin levels (follicle stimulating hormone(FSH) ＞25 U/L),and decreased oestrogen levels [1].Taking into account the differences in population and ethnicity,the current incidence of POI is approximately 1%to 7%[2-4].

Causes of premature ovarian insufficiency

The most common causes of POI include mainly congenital factors such as chromosomal and gene defects and acquired factors such as autoimmune disorders,radiotherapy,chemotherapy,infection,surgery,and adverse environmental exposures[5,6].

Chromosomal and genetic defects

Approximately 10% to 12% of POI patients have chromosomal abnormalities.Most of these abnormalities are X chromosome abnormalities (X chromosome structural abnormalities or X chromosome aneuploidy) [7,8],in which there is a deletion of part or all of one sex chromosome,such as that seen with Turner syndrome in the clinic.The presence of a Y chromosome in a small number of POI patients greatly increases the risk of developing gonadal tumours.Clinicians should advise patients to remove their gonads [9].Fragile X syndrome refers to the trinucleotide repeat CGG of the fragile X mental retardation gene (FMR1).Studies have found that the risk of POI is significantly increased with this repeat sequence[10].Autosomal gene mutations cause POI to be relatively rare,and occasionally,it can occur in patients with galactosemia diagnosed before puberty;however,there are differences in gene regulation pathways and the types of genes that cause POI in different ethnic groups[11,12].At present,research on the pathogenic genes of POI is based on researchers'knowledge that the gene plays a role in follicular development or ovarian function.There are as many as 100 candidate genes that have been confirmed to be related to POI.There are only two related genes,FMR1 and BMP15,and other candidate genes with uncertain mutations need to be further studied[13].

Autoimmune disorders

At present,it is believed that autoimmune POI is related mainly to autoimmune adrenal disease,thyroid disease,and type 1 diabetes,among other conditions[14,15].Of these,POI caused by autoimmune adrenal diseases accounts for 60% to 80% of cases and is the most common type of autoimmune POI [16].Additionally,Addison’s disease,an autoimmune condition,is the most clinically relevant disease to autoimmune POI [17].When there is a problem involving autoimmunity,POI is most often associated with thyroid autoimmunity [18,19].Welt et al.emphasized the close relationship between thyroid disease and POI and recommended that patients with autoimmune POI be tested for thyroid peroxidase antibodies (TPO-Ab) [20].For POI patients whose TPO-Ab screening results are positive,it is recommended that they be screened for thyroid stimulating hormone(TSH)every year.

Iatrogenic factors

Surgery,chemotherapy,and radiotherapy,among other medical procedures,are the main iatrogenic factors leading to POI [21-23].Ovarian endometriotic cysts,tumours,and unilateral or bilateral ovarian surgery,among other factors,directly affect the level of the ovarian blood supply and reduce the ovarian reserve[24-26].Radiotherapy and chemotherapy are used to treat malignant or benign diseases but lead to POI.The risk of POI caused by radiotherapy depends mainly on the site,dose,and age of the patient.Radiation can cause DNA damage,and its impact on mature follicles is more serious than that on primordial follicles.The older the patient is,the worse the tolerance to radiotherapy will be.Therefore,the ovarian tissues of younger patients are more tolerant of radiation than those of older patients.Chemotherapy and other drugs can induce oocyte apoptosis or destroy granular cell function and accelerate damage to ovarian function[27,28].

Infectious factors

According to case reports,the main infectious factors associated with POI include tuberculosis,chickenpox,mumps,cytomegalovirus,and HIV,among others [29,30].However,there is currently no definitive research on the diagnosis of infectious factors and POI.Therefore the use of infectious factors as routine screening indicators is not recommended in clinical practice.

Environment and other factors

Although there have been more in-depth clinical studies on the causes of POI,there are still some idiopathic POI patients for whom the cause of POI remains unclear.Studies have shown that smoking,alcohol abuse,malnutrition and exposure to endocrine disruptors may affect the age of menopause.Because smoking damages the ovaries,POI-prone women quit smoking as soon as possible,but there is no direct clinical evidence or report on the relationship between POI and smoking [17].In addition,excessive weight loss,frequent exposure to hair dyes or perm products,work with heavy metals,exposure to decoration materials or rubber,and exposure to antioxidants such as those in certain preparations can also cause oligomenorrhea and secondary amenorrhea.Studies have shown that exposure to ethylene glycol methyl,2,2-bis(bromomethyl),1,3-propanediol,and benzo[a]pyrene can cause POI in offspring[31-33].

Clinical manifestations of premature ovarian insufficiency

Menstrual changes

POI can be divided into two categories [34].The first category is primary POI with primary amenorrhea as the main clinical manifestation,and the second category is secondary POI,which is accompanied by a gradual decline in ovarian function and manifests mainly as oligomenorrhea,decreased menstrual flow,amenorrhea and irregular menstruation.A small number of women even have menstrual cessation.

Decreased fertility or infertility

In the early stage of POI,although the patient's fertility is reduced,there is still a 5% to 10% chance of natural pregnancy due to sparse ovulation [35].It is worth noting that at this stage,the foetuses of POI patients have on increased risk of chromosomal aberrations and spontaneous abortion of pregnancy.

Consequences of low oestrogen levels

Primary POI manifests mainly as poor or underdeveloped female secondary sexual characteristics.Secondary POI can temporarily or intermittently result in menopausal symptoms such as hot flashes and night sweats,loss of libido,vaginal dryness,osteoporosis,sleep disturbance,mood changes,inattention,and frequent urination.

Long-term management and outcome of premature ovarian insufficiency

Bone health

The beneficial effects of oestrogen on bone health have long been recognized,so the impact of related oestrogen deficiency caused by POI on bone health is one of the clearest adverse consequences of the disease[36-38].A lack of oestrogen can lead to increased bone remodelling,enhanced osteoclast activity and accelerated bone resorption.This in turn induces an increase in osteoblast activity and bone formation so that the rate of bone resorption exceeds the rate of bone formation and bone in the early postmenopausal stage (within 10 years of menopause).The net loss rate can reach 2% to 3% per year [39].Osteopenia/osteoporosis is the most common diagnosis,and the prevalence of osteoporosis in POI is approximately 8% to 14% [40,41].It is recommended that women adjust their lifestyles,by including weightbearing exercise,avoiding smoking and having a balanced diet to optimize bone health.At the same time,the intake of calcium (Ca) and vitamin D can be increased,hormone replacement therapy (HRT) can be used appropriately,or anti-osteoporosis treatment can be received.

Cardiovascular problems

Since the late 1950s,many scholars have recognized that premenopausal ovariectomy increases the incidence of cardiovascular disease in women[42].Studies suggest that loss of ovarian function and lack of endogenous oestrogen may lead to a higher risk of death from cardiovascular disease (CVD) among women with POI [43].In addition,premenopausal women with oestrogen deficiency will have vascular endothelial dysfunction [44]and signs of premature atherosclerosis [27].Turner syndrome (TS) is a special type of POI that has a variety of cardiovascular risk factors,including hypertension,obesity,impaired glucose tolerance and hyperlipidaemia [45].Among 1,400 TS patients,the CVD mortality rate is 4 times that of healthy women [46].In addition to avoiding high-risk factors that lead to CVD,it is recommended that POI patients adopt HRT therapy to reduce the risk of long-term CVD.Although therapy has obvious effects on blood pressure,blood lipids,endothelial function,and insulin resistance,among other physiological features,in the absence of long-term large-sample prospective data research,individualized treatment should be implemented in clinical practice.

Neurological problems

At present,few studies have directly explored the effects of POI on neurological function.Clinical evidence is divided into spontaneous POI and iatrogenic POI.Spontaneous POI includes genetic diseases and unexplained (idiopathic) POI.Iatrogenic POI includes mainly post-ovariectomy and follow-up treatment of breast cancer.Studies have shown that women with specific genetic diseases are more likely to develop POI.For example,compared with the control group whose age,height,IQ,and socioeconomic status are consistent with the baseline,TS patients have poorer average emotion recognition ability,attention,memory and executive ability [47].Compared with patients with premutation of the FMR1 gene,POI patients with full mutation of the FMR1 gene have significantly reduced intelligence,memory,and executive ability (excluding language ability) [48].Indirect evidence through observational studies suggests that the early age of natural menopause may be associated with an increased risk of dementia and cognitive impairment [49].Women who consider unilateral/bilateral oophorectomy for multiple reasons have an increased risk of dementia.Several retrospective studies have shown that patients with menopause caused by postoperative menopause are at a 1.68-fold increased risk of parkinsonism without HRT treatment [50].The use of hormones in the treatment of postmenopausal neurological function at any age is a topic of great concern,but at least before the average age of natural menopause,oestrogen replacement therapy should be considered for POI patients to reduce their possible cognitive impairment risk.

Sexual function and urogenital problems

Most of the existing research is aimed at middle-aged women with natural menopause,and there are few direct studies on POI and sexual relations.Women’s sexual behaviour may be affected by POI,but some patients bear more of a psychological burden,especially the resulting infertility.Systemic or local administration of oestrogen has a certain effect in improving sexual disharmony caused by low oestrogen due to POI.In addition,appropriate psychological counselling and emotional regulation for POI patients also have clinical significance.

Long-term hypoestrogenaemia can cause vulvovaginal atrophy,but there is no report on the incidence of urogenital symptoms in spontaneous urinary tract infections.Among patients with iatrogenic POI caused by breast cancer treatment,the incidences of moderate to severe difficulty and vaginal dryness are 42%and 49%,respectively [51].Vaginal lubricants,moisturizers and HRT (both systemic and topical) are used to treat reproductive and urinary system symptoms,such as vaginal dryness,decreased libido,frequent urination,and urinary incontinence.

Life expectancy and quality of life

POI affects not only women’s fertility but also women’s bone and cardiovascular health and nerve function.Realizing the long-term consequences of these effects has led to the hypothesis that POI may be associated with higher mortality.In addition,POI may be associated with many autoimmune diseases and may also be caused by cancer treatment or preventive resection in women at high risk of cancer,which may greatly affect mortality.POI itself is a disease that has a complicated onset,has a long treatment process,and affects multiple systems of the body.Therefore,it will inevitably have a certain impact on the patient’s own health-related quality of life.For confirmed POI patients,it is recommended to intervene both medically and psychologically to improve the woman quality of life.

Premature ovarian insufficiency and the need for infertility treatment

Psychological and lifestyle intervention

Women of childbearing age may experience greater psychological stress after being diagnosed with POI.Doctors and their family members should help relieve the mental stress of POI patients and guide POI patients who have fertility needs.Although ovarian function decline can lead to infertility,studies have shown that this disease still has a natural conception rate of 5% to 10% [35].Patients should maintain a good attitude,healthy eating habits,and regular exercise;should avoid smoking,alcohol,other bad habits,and contact with reproductive toxic substances;and actively participate in social activities.Those with a low bone mineral density (BMD) should also receive calcium and vitamin D supplementation.

Hormone replacement therapy

Hormone replacement therapy is currently a common method used to treat infertility caused by POI.This therapy plays an active role in the prevention and treatment of long-term complications of POI by alleviating the symptoms of oestrogen deficiency.Studies have shown that HRT can relieve vasomotor symptoms,reduce the incidence of fractures,and prevent cardiovascular disease,thereby improving the quality of life of POI patients[1].At present,studies have not found that HRT in patients with POI before the age of natural menopause increases the risk of breast cancer or endometrial cancer[52].Therefore,once it is clear that the patient has oestrogen deficiency,HRT can be based on the absence of contraindications and need for caution.One can start according to the corresponding treatment principles of HRT.After reaching the average age of natural menopause(approximately 50 years old),one can refer to the postmenopausal HRT programme to continue treatment.Clinical HRT regimens for the treatment of infertility caused by POI include oestrogen therapy alone,a continuous combination of oestrogen and progesterone,and sequential oestrogen and progesterone therapy.Commonly used oestrogens include 17β-oestradiol,conjugated oestrogen and transdermal oestradiol(should be adjusted individually according to the patient’s specific conditions),and the most commonly used progesterones are dydrogesterone,micronized progesterone capsules or methylhydroxyacetate.For progesterone treatments,compound preparations such as oestradiol-oestradiol dydrogesterone,oestradiol valerate-oestradiol valerate and cyproterone tablets can also be used.

Assisted reproductive technology

Developments in reproductive endocrinology have led to a new method for the treatment of POI,namely,assisted reproductive technology(ART)through ovulation induction treatments.However,ART relies on sound ovarian function and individual differences.It is difficult for physicians to identify the best ART medication regimen during treatment.Many physicians try to increase the dosage of gonadotropin and release of gonadotropin.Hormone agonists are currently used.Antagonists,micro-stimulation and natural cycles have a certain improvement effect [53],but egg donation in vitro fertilization-embryo transfer (IVF-ET) is an alternative for POI patients with fertility problems.The pregnancy success rate is the same as that of routine IVF-ET[54,55].

Fertility preservation

Based on the patient's wishes,age and marital status,combined with the opinions of embryology,genetics,reproductive medicine and other multidisciplinary consultations,fertility preservation methods have been formulated and implemented,which is suitable for POI high-risk groups and reproductive-age women with impaired ovarian function.Currently,the clinical fertility preservation methods include embryo freezing,ovarian tissue freezing,mature oocyte freezing,andin vitroimmature oocyte maturation technology.However,due to ethics,cost,technology,safety and other issues,fertility preservation methods have not been widely developed in China.As the technology is continuously improved,it is expected to benefit more women with high risk of POI.

Stem cell transplantation

Studies have found that there are two types of stem cells in the ovary,namely subcortical ovogenic stem cells and intraovarian mesenchymal stem cells,which plays an important role in oocyte formation and follicular development [56,57].Potential ovarian stem cells,obtained by follicular puncture,can differentiate into oocyte-like cellsin vitro,and express oocytespecific molecules (GDF9 and ZP3),which provides a new therapy approach for POI patients with reduced ovarian function to obtain oocytes [58].Among them,the transplantation of mesenchymal stem cells (MSCs)is most widely used and studied for clinical practice,including MSCs in bone marrow,peripheral blood,umbilical cord,placenta and amniotic fluid[59].

Conclusion

In general,POI infertility is currently seen as one of the most common gynecological diseases.As the national fertility policy and the change of reproductive desire of women of childbearing age continue to increase,it is urgent to explore new treatment strategies and methods for POI.Although the clinical evidence has showed that the pathogenesis of POI may be closely related to genetic defects,immune disorders,radiotherapy,chemotherapy,infection,environment and other factors,more than half of its related pathogenesis mechanisms are still unclear.At present,hormone replacement therapies are mainly used in the clinical treatment of POI patients,and assisted reproductive technology is beneficial to fertility.However,due to the influence of multiple factors,accurate and effective treatments for POI specific causes are very limited.In the future,the sample sizes of clinical and basic researches should be expanded in order to further clarify the cause of the disease and optimize its diagnosis and treatment plans.