Ovulation induction drugs and Discussion

Abstract: In recent decades, the development of reproductive endocrinology rapidly induce ovulation drugs is endless. Superovulation in breaking the the physiological cycle month row of the limitations of an egg, increasing the number of oocytes, and thus improve the pregnancy rate. With to ovulation drugs improvements and purified, to some extent reduce the side effects of the drug, but there are a lot of problems are not completely solved, such as endometrial development is not synchronized, luteal phase defect (LPD) and ovarian tumors. I mainly from The above problems starting to explore the status quo.

Keywords: ovulation induction hormones cytokines LPD

Mechanism based on the principle of superovulation superovulation technology oogenesis, the basic theory of the follicle, but different from the physiological cycle of ovulation. The oocyte development process roughly migration of primordial germ cells differentiate into primordial follicles, and then primordial follicles start growth and final maturation and ovulation are born approximately 30 to 500,000 the number of primordial follicles, maturation and ovulation, but about 400, so most of the follicles in the growth process occurs withered apoptosis and atresia. gonadotropin preparations and pituitary down-regulation of hormone application actually effectively control the number of follicles and egg quality super-ovulation process, as well as adjust the endometrial receptivity. hyperstimulation and ovulation induction. The latter is ovulation, irregular ovulation in patients by directly or indirectly stimulate follicular development, ovulation induction and get a single or a small amount of egg. while the former is for women with ovulation by stimulating the development of multiple follicles in ovarian, to get more The amount of eggs. clinical mainly through controlled ovarian hyperstimulation, in order to get the number right amount of eggs to meet the needs of IVF.

Ultra promote ovulation main problems 2.1 endometrial receptivity is not synchronized and embryo implantation obstacles in each menstrual cycle, ovulation endometrial only within a very short period of time [in the normal menstrual cycle of 20 to 7 to 11 days after the peak of the 24 days, luteinizing hormone (LH)] allowed the implantation of the blastocyst is called "implantation window" show the greatest blastocyst planting receptivity endometrial specific performance for the specific cellular and molecular sequence of events occurred, and subject to the regulation of cytokines, protein molecules. successful implantation depends on acceptance of maternal and embryonic invasive height during this period, especially in assisted reproductive technology (ART) coordination, ie follicles in vitro maturation must synchronized with endometrial development and implantation window "implanted in the womb, the matrix must be implanted in the womb dissolved trophoblastic can successfully implanted matrix metalloproteinase (MMPs) are a key enzyme involved in extracellular matrix degradation, to nourish the layer cell invasion behavior regulation therefore critical factor.

2.1.1 pinocytosis sudden. The pinopodes (Pinopode, pp) membrane protrusions appear in the the implantation window scanning electron microscope can see the top of the uterine lining epithelium cell membrane. Natural cycle, pinopodes the mature of time and human utero membrane implantation window period of time consistent with, and may be involved in the process of blastocyst implantation and is therefore considered a specific morphological signs of endometrial receptivity There are three theories on pinopodes affect pregnancy rate Develioglu [1] that the stimulation cycle, pinocytosis projecting now 1 to 2 days in advance, it may represent the endometrial implantation window the movement of the embryo and endometrial development are not synchronized, resulting in early implantation window open or closed late, so that The cycle of low implantation rates. Pauson RJ [2]: hormone replacement cycle pinopodes push accept donated eggs implantation rates tend to be higher than the the line controlled ovarian hyperstimulation (COH) oocyte donation. Crues M [3] clomiphene ovulation induction thus affecting the pregnancy rate by reducing the number of endometrial pinopodes.

2.1.2 The hormone the mammalian blastocyst implantation. Ovarian steroid hormones (E2/P4) with a start, ready for the implantation of the blastocyst. Follicular phase estrogen regulation of uterine epithelial cell proliferation, the corpus luteum of progesterone can start stromal cell proliferation, estrogen strengthen stromal cell proliferation, epithelial cells stop proliferation in the differentiation state of the stromal cells of the blastocyst sites at widely proliferation and differentiation into decidual cells, endometrial Yung sexual establish specific mechanisms for estrogen and progesterone receptors (ER, PR) down, PR lowered directly related integrin @ vβ3 integrin @ vβ3 considered endometrial receptivity labeled molecules. P4 can the projections pinocytosis induced endometrial epithelial cells appear. Ozcakir study found that GnRH-a process of controlled ovarian hyperstimulation, the day of HCG the serum P/E2 the ratio> 1, may occur occult LH peak, follicle over early luteinized poor clinical outcome; serum E2 / P ratio increased significantly in the 4.32 to 6.11 range, clinical pregnancy rate, similar to the results of the previous studies. ovarian response in IVF-ET cycles, E2 too high or P is the relative lack of or improper E2 / P ratio, can reduce endometrial receptivity to embryo implantation failure [5].

2.1.3 cytokines in endometrial expression of cytokines in the formation of endometrial receptivity, embryo implantation is closely related to IL-1 and IL-6. Scholars believe that [6], IL-1 epithelial cells can be induced to increase expression of adhesion molecules, increased epithelial adhesion of the blastocyst regulate endometrial receptivity Another study found that endometrial epithelial cell expression of IL-1β and leptin (leptin) can increase the expression of the integrin and IL-1β also increased the expression of leptin and its receptor, thus indicating that leptin effector molecules IL-1β regulation the integrin β3 role in both in the womb play an important role in the formation of membrane receptivity and embryo implantation. IL-6 has the ability to directly regulate the blastocyst through the epithelial cell basal on the one hand, in addition to also stimulate the synthesis and secretion of endometrial chondroitin sulfate proteoglycans , which plays an important role in the growth and implantation of the blastocyst, and IL-6 as well as the role of immune nutrition, conducive to pregnancy and normal placental growth and development, implantation window period, the higher levels in endometrial secretion inhibit cell immune response cytokines play a leading role.

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2.1.4 Protein integrins (integrins) is commonly found in cell surface transmembrane glycoprotein, belongs to a large family of cell adhesion molecule expression characteristics sex changes and trophoblastic invasion parallel, thereby speculate the disintegrin @ υβ3 maternal trophoblastic initial contact process, may be involved in the establishment of endometrial receptivity, integrin as the evaluation of endometrial receptivity The study found that a useful marker 9]. Thomas and other women after pregnancy after IVF endometrial @ υβ3 expression levels were significantly higher than the non-pregnant group, and the @ υβ3 positive expression group pregnancy rate of 47% was significantly higher than Engmann recent statistics two IVF cycles average pregnancy rate of 38.2%.

Placental protein is a glycoprotein secreted by the surface of the endometrium, studies suggest that the placental protein can be provided by suppressing the maternal endometrial natural killer (NK) cell activity, so as to achieve the purpose of the endometrium from rejection embryonic. Placental protein 14 is relatively low concentration was abnormal embryo implantation and pregnancy researchers pointed out that serum placental protein 14 is the most reliable evaluation of endometrial function - the regulation might affect the formation of endometrial receptivity to embryo implantation. indicators. study also found that irregular menstrual vaginal bleeding and serum placental protein 14 concentration decreased women, the probability of suffering from habitual abortion five times the normal menstrual normal placental protein 14 women. semen placental protein 14 with parent endometrial secretion of placental protein 14 to promote the formation of endometrial receptivity, implantation of fertilized eggs and placental development, inhibit the maternal anti-fetal allotypes antigen, immune rejection.

The endometrial receptivity get by non-adhesion status endometrial become the adhesion state, mucin (Muc1) is an anti-adhesion molecules inhibit implantation embryo nourishes the top of layer of epithelial cells and endometrial epithelial adhesion role. endometrial receptivity period Muc1 disappear, which is considered to be one of the necessary conditions for the establishment of embryo implantation environment.

The matrix metalloproteinases (MMPs) are the most important enzyme in the degradation of extracellular matrix, and tissue inhibitor of metalloproteinase (TIMPs) combine to form a substantially irreversible complex in a 1:1 ratio. Gelatinases MMP-2 and MMP-9 is a key enzyme involved in cell nourishing and cell invasion, and they depend on the metal zinc ions, calcium ions are involved in the activity. Whiteside, MMP-9 and TIMP-3 interaction key factor in implementing appropriate cytotrophoblast invasion force. regulation of MMPs and TIMPs imbalance may cause cells to trophoblast invasion force anomalies, such as the invasion force, recurrent miscarriage, pre-eclampsia, intrauterine growth restriction, increased risk of pregnancy-induced hypertension disease invasion excessive, choriocarcinoma increase the likelihood of occurring.

2.2 LPD LPD is the development and function of the corpus luteum insufficiency, inadequate secretion of progesterone, poorly differentiated endometrial syndrome associated with menstrual disorders. The normal luteal embryo implantation and maintenance of pregnancy essential cause LPD in COH , resulting in the pregnancy rate decreased the LPD can cause recurrent spontaneous abortion women of childbearing age, the incidence is as high as 23% to 67%. LPD, there is no unified, accurate diagnostic criteria, the more recognized consistent luteal phase three consecutive determination as to how to determine progesterone levels <15ng/ml. ovarian stimulation for multiple follicular development and early luteal serum estrogen concentrations abnormally elevated progesterone concentrations in advance increased from proliferative phase endometrium into secretory phase, "planting window" opened up ahead on and off, the receptivity of the endometrium to reduce excessive estrogen and (or) progesterone negative feedback inhibition of LH secretion, premature luteolysis, luteal dysplasia egg retrieval process sucked out of oocyte The cells also bring out some of the granulosa cells, luteal cells produce hormones reduce about the LPD treatment has molding set programs, but each program has its own side effects, to find the exact cause of the LPD, further understanding of LH in COH in the role, the key to the prevention of the occurrence of LPD is luteal support.

2.4 ovarian tumors. Superovulation incidence of some tumors, especially with estrogen-dependent breast, ovarian and uterine cancer is closely related to. Recently there is a lot of research to explore the the ovulation induction offspring tumor whether to increase the risk of ovarian cancer is the most common cause of death in gynecological malignancies. infertility itself is an independent risk factor for ovarian cancer in, especially nulliparous women, refractory infertility by which patients are most likely to accept promote the treatment of fertility drugs, and thus appears to promote superovulation drugs and ovarian cancer have a significant relationship.

3 Conclusion In recent decades, reproductive endocrinology rapid development is endless only .20 1930s clinical application of estrogen and progesterone to induce ovulation, ovulation induction drugs, non-steroid anti-estrogen drugs in the late 1950s clomiphene 1960s purification of pure menstrual gonadotropin (hMG), 70, began using the gonadotropin-releasing hormone (GnRH) and bromocriptine, clinical trial GnRH analogues in the late 1980s, growth hormone (GH) and other combination of ovulation induction drugs to increase ovulation induction success rate of ovulation induction drugs widely used greatly advance the treatment of infertility, and brings hope for the majority of infertility patients, however, its side effects and complications brought risks are also increasingly concerned about how to prevent inadequate luteal function: avoid the LH surge, to reduce the abortion rate; effectively promote multiple follicular development at the same time, how to improve the quality of oocytes, reach and endometrial development synchronization to improve the pregnancy rate, and many other issues also worthy of further study in clinical work, we must fully understand the cause of the patient's pathogenesis and response to drugs to overall judgment and reasonable choice of drugs, the development of ovulation induction, strictly mastered ovulation drug indications, to prevent and treat complications, careful selection of new drugs, the most critical is individualized to achieve medication.

References

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[2] Pauson RJ, Sauer MV, Lobo RA. Potential enhancement of endometrial recepetivity in cycles using controlled ovarian hyperstimulation with antiprogestins: a hypothesis [J]. Fertil Steril, 1997,67 (2) :321-325.

[3] Crues M, Ordi J, FbareUges F, et al. The effect of different hormone therapies on integrin expression and pinopode formation in the human endometrium: a controlled study [J]. Hum Reprod, 2003,18 (4): 683 -693.

[4] Aghajanova L. Leukemia inhibitory factor and human embryo implantation [J]. Ann NYAcad Sci ,2004,1034:176-183.

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