Ovulation induction treatment is an important component of a series of assisted reproductive technologies such as artificial insemination (IUI) and in vitro fertilization-embryo transfer (IVF-ET). Ovulation induction (OI) refers to the application of drugs or surgery to induce ovulation in patients with ovulation disorders, usually with the aim of inducing the development of a single follicle or a few follicles. Controlled ovarian stimulation (COS) refers to the induction of multiple follicle development and maturation by pharmacological means within a controlled range, usually in patients with normal ovulatory function. The introduction of hyperovulatory techniques has played an important role in increasing the pregnancy rate in IVF, but the consequent problems have also received increasing attention. This article focuses on the possible adverse effects of ovulation-promoting drugs on patients from the perspective of drug mechanism of action. Commonly used ovulation-promoting drugs include clomiphene (CC), gonadotropins (Gn), chorionic gonadotropins (HCG) and gonadotropin-releasing hormone analogs (GnRHa). In recent years aromatase inhibitors such as letrozole (LE) for the treatment of estrogen-dependent disorders have received much attention as ovulation promoters and their adjuvant drugs. Among them, CC, LE and Gn are mainly used to promote follicle development; HCG is to promote the final maturation and ovulation of eggs; GnRHa is mostly used to carry out pituitary descending regulation, play pituitary inhibitory effect and avoid the endogenous LH peak to adversely affect eggs. 1.Clomiphene (CC) Effects and principles: The main component of CC is clomiphene citrate, which is a non-steroidal compound derived from triphenylene, commonly used preparations consist of about 38% cis-isomer and about 62% trans-isomer. The trans-isomer has both anti-estrogenic and weak estrogenic effects, while the cis-isomer is completely anti-estrogenic. CC exhibits both strong anti-estrogenic and weak estrogenic effects. Firstly, the anti-estrogenic effect predominates by competitively occupying hypothalamic estrogen receptors, interfering with the negative feedback of endogenous estrogen and inducing increased secretion of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) to stimulate follicle growth. After follicle maturation, the release of estrogen increases and induces ovulation by stimulating the release of pre-ovulatory Gn to peak through positive feedback.CC also acts directly on the ovaries to enhance the sensitivity of granulosa cells to pituitary Gn and the activity of aromatase. Effects: CC side effects are generally mild and may include flushing, ovarian enlargement, abdominal discomfort, occasional blurred vision, nausea, vomiting, headache, fatigue, etc. The symptoms may disappear spontaneously after several days or weeks of discontinuation without permanent damage. The anti-estrogenic effect of CC is manifested by hot flashes on the day of administration and by changes in cervical mucus and endometrium after 3-5 days, which can also affect the thickness of the endometrium. Therefore, when CC-containing microstimulation regimens are used, embryo transfer is generally not performed during egg collection cycles in order to prevent the anti-estrogenic effects of CC on the endometrium. When CC is used together with estrogen, its effect on endometrial thickness can be attenuated. 2. Letrozole (LE) Effects and principles: By blocking estrogen production and lowering estrogen levels, LE can release the negative feedback inhibition of the hypothalamic-pituitary-gonadal axis by estrogen and induce an increase in Gn secretion, which in turn promotes follicular development. Blocking the conversion of androgens to estrogens at the ovarian level leads to the accumulation of androgens in the follicles, which enhances the expression of FSH receptors and contributes to follicular development. At the same time, the accumulation of intrafollicular androgens stimulates increased expression of insulin-like growth factor-I (IGF-I) and other autocrine and paracrine factors, and increases ovarian responsiveness to hormones at the peripheral level via the IGF-I system. Effects: LE is well tolerated in clinical applications, the main side effects are gastrointestinal reactions, other side effects include hot flashes, headache and back pain. Gn includes follicle stimulating hormone (FSH), luteinizing hormone (LH) and chorionic gonadotropin (HCG). Gn drugs mainly promote follicular recruitment, stimulate follicular development and maturation, induce ovulation and corpus luteum formation by mimicking the physiological effects of FSH and LH for the purpose of ovulation induction and superovulation. Effects: 1) Increase the incidence of ovarian hyperstimulation syndrome (OHSS) During ovulation promotion with Gn drugs or CC+Gn drugs, some patients who are sensitive to Gn (especially with inappropriate high doses of Gn) will experience excessive follicular development and are at risk of OHSS after HCG injection, manifesting as abdominal distention, abdominal pain, ascites, pleural fluid, shock, thromboembolism, and The incidence of OHSS is about 20%, and there is no specific treatment available, so prevention is important. 2) Increased risk of multiple pregnancies and related maternal and infant risks In the natural follicular development cycle, 99% of follicles mature and are fertilized, resulting in a singleton pregnancy, while 1% of follicles mature and ovulate with 2 or more follicles, resulting in multiple pregnancies if fertilized simultaneously. Ovulation treatment can significantly increase the number of follicles developing at the same time, and ovulation induction can also significantly increase the incidence of fertilized egg division, making the chance of a monozygotic twin pregnancy 7-8 times higher than that of a natural pregnancy. The use of various ovulation-promoting drugs is an important reason for the increased incidence of multiple pregnancies, with higher rates of multiple follicle development and multiple pregnancies in Gn-sensitive patients. Multiple pregnancies and deliveries increase the incidence of maternal and infant complications, including miscarriage, preterm delivery, intrauterine growth retardation, gestational hypertensive syndrome, lack of contractions, surgical delivery, and postpartum hemorrhage. The incidence of intrauterine fetal death, low-body mass babies and neonatal asphyxia is also significantly higher, and the perinatal mortality rate is 4-10 times higher than that of singleton delivery. 3) Concurrent intrauterine and extrauterine pregnancies The incidence of concurrent intrauterine and extrauterine pregnancies in natural pregnancies has been reported to be 1/5000-1/15000, while the incidence of concurrent intrauterine and extrauterine pregnancies in assisted reproductive technologies is as high as 1.2%. It has been reported in the literature that the rate of simultaneous intrauterine and extrauterine pregnancies is 10 times higher with Gn-induced ovulation than with CC alone. Therefore, it is speculated that the possible causes are related to ovulation induction, transfer of multiple embryos and changes in hormone levels. Changes in sex hormone levels affect the proliferation of the tubal lining on the one hand and interfere with the function of the fallopian tubes by altering the contraction of the tubal muscles which control the transport process of the embryo through the fallopian tubes on the other hand. 4) Relationship with certain tumors It is now believed that superovulation is associated with the development of some tumors, especially closely related to estrogen-dependent tumors of the breast, ovary and uterus. Hyperovulation provides a high gonadotropin and estrogen environment that theoretically increases the risk of tumors in the female reproductive system, but there is no conclusive evidence on the relationship between ovulation promotion and tumorigenesis in the ovary, uterus, and breast. There is a lack of strong evidence that hyperovulation is associated with tumors. However, monitoring should be strengthened in those with high risk factors for tumor development, long-term use of ovulation-promoting drugs, multiple egg donors, those with persistent ovarian enlargement or ovarian cysts after ovulation promotion, and those with a family history of cancer. 5) Allergic reactions Since Gn is a protein and urinary extracts of Gn also contain many other urinary proteins, there is a risk of allergic reactions to large doses of long-term repeated use. Very few patients may develop hypothermia during injection, and redness, swelling and pain may appear locally at the injection site. In addition, there are reports of anaphylactic shock syndrome in some cases. GnRH-a is divided into GnRH agonist (GnRH-agonist) and GnRH antagonist (GnRH-antagonist) according to its mode of action with the receptor. GnRH-a binds to the GnRH receptor to form a hormone complex, stimulating a dramatic release of pituitary Gn and a 4-fold or more rise in serum FSH, LH, and estradiol (E2 ) within 12 h of the first dose. If GnRH-a is used continuously, the number of GnRH receptors that can be bound on the pituitary cell surface decreases and becomes insensitive to further GnRH-a stimulation, i.e. the so-called down-regulatory effect, leaving FSH and LH secretion at low levels, follicular development stalled and sex hormone levels decreasing, reaching pharmacological pituitary-ovarian deactivation in 7-14 days with the drug, thus serving as the basis for clinical application. Pituitary function is fully restored after discontinuation of the drug, and the recovery of ovarian function takes about 6 weeks after discontinuation in women with normal menstrual cycles. Effects: Long-term use of GnRH-a may result in symptoms associated with low estrogen, manifesting as hot flashes, excessive sweating, sleep disturbances, fatigue, irritability, and anxiety. In addition, it has been suggested that the “flare up” effect of GnRH-a increases serum progesterone levels and affects tubal peristalsis and cilia activity, which may be associated with the development of ectopic pregnancy. In a long regimen starting in the luteal phase, the initial “flare up” of GnRH-a administration may lead to the formation of functional ovarian cysts.