Premature ovarian failure is the phenomenon of amenorrhea before the age of 40 caused by ovarian failure. It is characterized by primary or secondary amenorrhea accompanied by elevated blood gonadotropin levels and decreased estrogen levels, and a series of hypoestrogenic symptoms of varying degrees of severity, such as hot flashes, excessive sweating, facial flushing, and low libido. The average age of natural menopause in women is 50-52 years old, and there are differences in the age of menopause in terms of race and regional distribution, but their absolute values do not differ much.Coulam et al. summarized the natural amenorrhea in 1858 women, and the incidence of POF was 1% in those less than 40 years old, and 1 per 1,000 in those less than 30 years old. POF accounted for 10-28% of primary amenorrhea and 4-18% of secondary amenorrhea. Xu Ling et al. found that the incidence of POF in women in Beijing was 1.8%. This shows that POF is not uncommon in clinical practice. Initially, POF was thought to be irreversible because early studies suggested that a serum FSH >40 IU/L meant that the absence of primordial follicles could lead to permanent infertility. This claim of permanent loss of ovarian function was challenged in later reports. Intermittent ovulation is observed in about 50% of patients with POF, and 5-10% have intermittent return of menstruation or even spontaneous pregnancy after diagnosis. Clinical manifestations Because premature ovarian failure can be caused by a variety of causes, its clinical manifestations are also different. Symptoms 1. Amenorrhea There are primary amenorrhea and secondary amenorrhea, and secondary amenorrhea occurs before the age of 40. Through the investigation of a large sample of POF patients, it is found that there is no characteristic aura of menstrual abnormality before amenorrhea. Some people have sudden amenorrhea after regular menstruation, some have amenorrhea after stopping birth control pills or giving birth, and some have disorders of menstrual cycle and menstrual period before amenorrhea. Infertility Some patients are found to have premature ovarian failure due to infertility. Infertility is the main reason for patients with premature ovarian failure to consult the doctor and suffer. There are primary infertility and secondary infertility, so it is recommended that people with family history of premature ovarian failure should plan pregnancy as early as possible. Low estrogen symptoms Low estrogen symptoms (hot flashes and/or difficulty in sexual intercourse, etc.) are rare in primary amenorrhea (22.2%), and most of them, if any, are related to previous estrogen replacement therapy, while low estrogen symptoms are common in secondary amenorrhea (85.6%). This is consistent with the theory that hypoestrogenic symptoms are caused by estrogen withdrawal. These hypoestrogenic symptoms also include atrophic vaginitis and atrophic urethritis such as frequent and painful urination. 4, accompanied by autoimmune diseases such as Addison’s disease, thyroid disease, diabetes, lupus erythematosus, rheumatoid arthritis, vitiligo and clonal disease. There are also insidious symptoms of adrenal insufficiency, such as recent weight loss, loss of appetite, unspecified abdominal pain, debility, increased skin pigmentation and salinity. 5.Natural recovery of intermittent ovarian function In 1982, Rebar et al. reported 26 cases of POF diagnosed by single FSH>40IU/L, of which 9 cases had follicular function, 5 cases had ovulation, and 1 case was pregnant. Thereby emphasizing that using a single FSH>40IU/L as evidence of follicular failure is erroneous. Several subsequent studies have confirmed that chromosomally normal POF patients still have intermittent recovery of ovarian function (including those with 2 or more FSH elevations). Vaginal ultrasound reveals follicular structure in 30-40% of patients, follicular function in 50% of patients by serum E2>50pg/mL, and ovulation in 20% of patients by serum P>3ng/mL. Therefore, premature ovarian failure is not equivalent to complete loss of ovarian function, and transient or intermittent recovery of ovarian function is possible.Patients with POF still have a 5%-10% chance of becoming pregnant after diagnosis. Disease treatment For a young POF patient, POF brings not only physical effects, but also more serious psychological effects, especially when they hear that there is no cure for premature ovarian failure and it cannot be reversed, it is like a thunderbolt in the sky for those who have not yet given birth, which means that it is impossible for them to have their own children in the future, and this kind of pain is imaginable. The pain is imaginable. What comes next is complaints to themselves and their families, such as they shouldn’t have seen a doctor so late, shouldn’t have used contraception, shouldn’t have had an abortion, and their parents’ genes are not good, and so on. Indeed, to date, there is no proven effective treatment to restore or protect ovarian function in most cases of unexplained idiopathic POF, with the exception of ovarian resistance syndromes caused by definite autoimmune diseases that can be treated with immunosuppressive therapy with positive results. In fact, it is a waste of time and money to spend a lot of time and money on ovulation induction with no results. Therefore, for patients with premature ovarian failure, the most important treatment is estrogen-progestin replacement therapy to alleviate symptoms, prevent long-term complications (osteoporosis, cardiovascular disease, premature dementia, etc.), and prevent uterine atrophy (in preparation for egg transfer), as well as psychological treatment to change the mindset, and for women who have not had children, do not blindly expect the unattainable restoration of ovarian function or even pregnancy. Women who have not had children should not blindly expect the recovery of ovarian function or even pregnancy, but should undergo embryo transfer at a suitable time that is acceptable in terms of both conception and economy. Estrogen and progesterone replacement therapy (HRT) Estrogen and progesterone replacement therapy is very important for young patients with POF, i.e., it can alleviate the symptoms of hypoestrogenism and atrophy of the genitourinary tract (in preparation for donor egg transfer), and also prevent long-term complications (osteoporosis, Alzheimer’s disease, etc.) and reduce the risk of colon cancer by 37%. However, long-term HRT also carries certain risks, such as the development of endometrial and breast cancer, but studies have shown that estrogen-progestin replacement therapy when progestin is applied for more than 10 d per month reduces the risk of endometrial cancer to almost zero, and the risk of breast cancer is slightly increased, but the mortality rate is not increased. A sequential combined estrogen and progestin regimen is usually used. Prevention of osteoporosis: in addition to HRT, ensure daily calcium intake of 1200mg. VitD 400-800IU/day, and perform necessary physical exercise such as walking, yoga or Tai Chi. In patients with POF, the HRT estrogen dosage should be more than in menopausal women because younger patients with POF need more estrogen to relieve vasodilatory symptoms and maintain normal vaginal mucosa. Therefore, estrogen preparations are usually used for a total of 21 d/month, with progestins added for the last 10 d. Estradiol valerate is a natural estrogen with the same efficacy and pharmacokinetics as E2, which is more physiologic, so it can be recommended for women planning pregnancy. Many literatures report ovulation or pregnancy in POF patients during HRT treatment or in the short term after discontinuation of the drug. The possible mechanism is also explained to be that estrogen reduces high circulating levels of FSH through negative feedback, thereby deregulating the hypergonadotropic gonadotropin down-regulation of gonadotropin receptors in the granulosa cells, and with an increase in receptors, the residual follicles within the follicle regain sensitivity to gonadotropins, thereby increasing the likelihood of ovulation and pregnancy. Ovulation promotion therapy Most of the conditions for screening patients before treatment are short duration of amenorrhea, not too high blood FSH level, and clinical judgment of follicular POF. Generally, after suppressing endogenous gonadotropins (mainly FSH) with HRT or GnRHa to a low level (<20IU/L), sufficient amount of hMG/hCG is given to promote ovulation with ultrasound monitoring, which requires a high dosage of hMG and a long duration. There is no good reason to blindly recommend the use of gonadotropins for ovulation. A more correct approach should be to advise patients to come to the hospital for follicle monitoring when they feel symptoms of estrogen increase (e.g. increased vaginal discharge, breast swelling and pain, etc.). If dominant follicles are detected, depending on the patient's condition, active measures can be taken to guide the patient to cohabitate or undergo IUI or natural cycle/improved natural cycle of IVF, so that they can seize this rare and hard-won opportunity in a timely manner. Immunotherapy Since immune factors are a definite cause of premature ovarian failure, immunosuppressive therapy is effective for this group of patients with evidence of immune factors. In patients with chromosomal karyotype normal premature ovarian failure, treatment with dexamethasone and ovulation induction after pituitary down-regulation may be beneficial in the restoration of ovarian function. DHEA treatment DHEA is 50% secreted by the reticular zona of adrenal cortex, 20% secreted by the ovary, 30% converted by peripheral DHEAS, the body produces 6-8mg per day, the blood concentration of 3-35nmol/L, and its level decreases with age.DHEA is an important substance for the synthesis of androstenedione, testosterone, and estradiol, and the level of DHEA influences the level of these hormones. DHEA is an important substance for synthesizing androstenedione, testosterone and estradiol. Side effects of DHEA are minimal and, if used in high doses, include acne, facial hair growth and occasional thickening of the voice. Regarding its safety, a randomized, double-blind study of DHEA applied at 50 mg/d for 52 weeks did not find any effects on lipid metabolism or insulin resistance, and no negative effects on the endometrium were found. DHEA should be applied under the guidance of a reproductive specialist, who should be aware of the dose and duration of application. Generally 50-75 mg/d is applied for 2-4 months and should be discontinued once pregnancy has occurred. Future randomized controlled studies with larger samples are needed to confirm these results. Egg donation embryo transfer The source of egg donation is even more limited as our Ministry of Health has restricted the source of egg donation in the future to residual oocytes obtained by assisted reproduction techniques.The study by Remohi et al. found that appropriately prolonged estrogen replacement waiting for residual donated eggs for IVF did not affect the success rate. It also significantly reduced the cycle cancellation rate for recipients (switching to frozen embryos) and increased the chances of fresh embryo transfer. However, the authors note that estrogen replacement should not be done for more than 9 weeks or breakthrough bleeding is likely to occur.