What Are Ovulation Kits?

Western medicine and traditional Chinese medicine are used to promote ovulation. Western medicine mainly achieves the goal of promoting ovulation by regulating the "hypothalamic-pituitary-ovary" axis. Traditional Chinese medicine mainly promotes ovulation by invigorating the kidneys and treats ovulation disorders.

Western medicine and traditional Chinese medicine are used to promote ovulation. Western medicine mainly achieves the goal of promoting ovulation by regulating the "hypothalamic-pituitary-ovary" axis. Traditional Chinese medicine mainly promotes ovulation by invigorating the kidneys and treats ovulation disorders.

Drug Name

Ovulation medicine

Alias

Ovulation-promoting drugs

Foreign name

ovulation drug

Whether prescription drugs

prescription

Main indications

Infertility caused by anovulation in female patients

Dosage

Follow the doctor's order

Whether to include health insurance

Not included

Ovulation Drugs I. Overview

Infertility is a condition in which a woman fails to conceive for two years without taking contraceptive measures. Research data from the World Health Organization show that about 12% to 16% of couples worldwide are infertile, and infertility caused by ovulation disorders accounts for 31% to 40%. Promoting ovarian function and inducing ovulation are important methods for treating infertility caused by ovulation disorders. The medicines used for treatment are western medicine and traditional Chinese medicine. Western medicine mainly promotes ovulation by regulating the "hypothalamic-pituitary-ovarian" axis. Traditional Chinese medicine mainly promotes ovulation by invigorating the kidneys and treats ovulation disorders.

Ovulation drug II. Ovulation mechanism

Hypothalamic gonadotropin (GnRH) secretion is a very important prerequisite for pituitary gonadotropin secretion; but the feedback mechanism that regulates gonadotropin levels is controlled by ovarian pituitary hormones. Estrogen and progesterone not only affect the hypothalamus through the catecholamine system, but also directly affect the anterior pituitary. The catecholamine system has a dual function: norepinephrine promotes it, while dopamine inhibits the secretion of GnRH ^[1] .

( 1) The role of estradiol (E ₂ ) in the normal menstrual cycle-the release of negative feedback and the occurrence of positive feedback:

Before the end of the menstrual cycle, due to atrophy of the corpus luteum, estrogen and progesterone decline, the negative feedback effect on the hypothalamus and pituitary is released, and the secretion of follicle maturation hormone (FSH) increases. FSH is indispensable for follicular development and steroid synthesis. Growing follicles continuously secrete E ₂ , which promotes FSH receptors and promotes follicle sensitivity to FSH. E ₂ also cooperates with FSH to make luteinizing hormone (LH) receptors appear on the granule layer. If the amount of FSH is low, luteal dysfunction or short luteal phase will occur. Mature follicles secrete a large amount of E ₂ , which causes the E ₂ level in the bloodstream to rise sharply, which plays a positive feedback role on the hypothalamus and pituitary gland, leading to a peak of LH before ovulation. 24 to 36 hours before ovulation, the amount of blood E ₂ reached a peak, about 200 pg / ml, and maintained for about 50 hours. If the amount of E ₂ is too low or the peak time is too short, the LH peak may die or not occur. The peak of LH occurs 10 to 12 hours before ovulation, which is a reliable indicator of ovulation. After ovulation, the corpus luteum is formed, and a large amount of progesterone and E _{2 are} continuously secreted, which negatively affects FSH and LH. FSH and LH decreased, but still maintained a certain level to support luteal function. However, the corpus luteum has a certain life span, gradually becomes insensitive to FSH and LH and shrinks, and the secretion of estrogen and progesterone decreases. Due to the release of E ₂ 's negative anti-angry effect on the hypothalamus and pituitary, FSH and LH gradually increased again, and another menstrual cycle began again.

( B) Pulsed secretion of hypothalamic gonadotropin (GnRH):

In the past, female hypothalamus was thought to have a tension center located in the arcuate nucleus and a periodic center located in the preoptic nucleus, respectively, to control the release of GnRH. It has been found that there are no two centers in primates. Results obtained from experiments that break the hypothalamus or block the connection between the hypothalamus and the pituitary:

(1) Only the destruction of the arcuate nucleus in the lower thalamus can lead to gonadal atrophy and amenorrhea. The arcuate nucleus and median bulge can be regarded as a unit that secretes GnRH;

(2) GnRH can only be recovered by pulsed intravenous infusion of GnRH instead of continuous administration.

(3) At the same time as the above administration, adding different doses of E: can cause a positive-negative feedback response, indicating that E ₂ can directly affect the pituitary.

(3) Dysfunction in any part may lead to anovulation, which may lead to amenorrhea, thin menstruation, dysfunction, etc., leading to infertility:

(1) There are two types of hypothalamic disorders: functional and organic. The former includes idiopathic intercranial amenorrhea, psychogenic amenorrhea, functional hyperprolactinemia, and anorexia nervosa; the latter includes intercranial tumors, after encephalitis, and after head trauma.

(2) Pituitary dysfunction. Pituitary adenoma, Sheehan syndrome, tuberculosis or syphilitic granuloma.

(3) Ovarian dysfunction includes primary and secondary amenorrhea of the ovary. The former includes Turner syndrome. The latter includes premature ovarian failure, organic damage to the ovaries, such as loss of function after radiation exposure, and damage caused by tumors and inflammation.

Ovulation drugs III. Common ovulation drugs

Clomiphene

Clomiphene (CC), also known as clomiphene, is a non-steroidal compound with a chemical structure similar to that of chlorestrel, with moderate anti-estrogen and weak estrogen effects. CC competes with endogenous estrogen receptors and has a stronger affinity. By competitively binding to the estrogen receptor in the hypothalamus, the target cells are insensitive to estrogen, which relieves the negative feedback effect of estrogen on the hypothalamus, and the frequency of release of hypothalamic gonadotropin-releasing hormone (GnRH) increases Furthermore, the pituitary releases FSH and LH. FSH promotes follicle development and maturation, the rise of pre-ovulation estradiol (E2) levels causes a positive feedback effect, and promotes the central frequency of GnRH release, and the pituitary releases FSH and LH rapidly increase, especially LH, forming LH peaks and inducing ovulation ^[2] .

The clinical effect of CC ovulation promotion has been widely studied and reported. It is suitable for infertile women with hypothalamic-pituitary-ovarian gonadal function weakened or uncoordinated, follicular development disorders, and hypogonadal pituitary failure-induced gonad function. Lowness is its best indication. The dosage and usage should be individualized and adjusted appropriately with changes in gonad axis function. In general, the ovulation rate is 70% to 90%, the pregnancy rate is 30% to 40%, the pregnancy rate with an ovulation cycle is 20% to 25%, and the abortion rate is 20%, which is slightly higher than that of natural pregnancy. Rate (12% to 15%).

Gonadotropin

Human gonadotropin (Gn) mainly includes FSH, LH secreted by the pituitary gland and human chorionic gonadotropin (HCG) secreted by the placenta, which are all glycoprotein hormones. Gn enhances follicle recruitment and growth during follicular development, stimulates follicle growth and maturation, FSH promotes aromatase activity in granular cells, converts androgens to estrogen, increases estrogen levels and Promote endometrial proliferation and can be used to induce ovulation or superovulation. FSH and LH work together to stimulate the proliferation and differentiation of various cells in the follicle and stimulate the growth and development of the follicle. LH mainly stimulates follicular membrane cells to produce androgens, which are substrates of aromatase. Therefore, LH and FSH play a role in estrogen production, and promote the final maturation of follicles and oocytes, trigger ovulation, promote the formation of the corpus luteum, and maintain the function of the corpus luteum. Products currently in clinical application include HCG extracted from the urine of pregnant women, human menopausal gonadotropin (HMG) extracted from the urine of menopausal women, and human follicle stimulating hormone (u-FSH) extracted and purified from the urine, highly purified Human follicle stimulating hormone (u-FSHHP), and recombinant FSH (rFSH) and LH (r-LH) produced by genetic recombination engineering technology.

At present, HCG and HMG are mainly used in clinical practice. HCG can promote and maintain the corpus luteum function, make the corpus luteum synthesize progesterone, can promote follicle generation and maturity, and can simulate the peak of physiological luteinizing hormone to promote ovulation; HMG has the role of FSH to promote the maturation of follicles in the ovary And make the endometrial hyperplasia. The combination of the two can be used for anovulatory infertility caused by insufficient gonadotropin secretion.

3.GnRH and its analogs

GnRH, also known as luteinizing hormone releasing hormone (LHRH), is a 10-peptide that can be artificially synthesized. The amino acid arrangement in its structure is as follows: Jiaogu-group-color-filament-casein-bright-crystal-proline-glycan Endogenous GnRH is synthesized in the arcuate nucleus of the medial basal area of the hypothalamus and GnRH cells in the preoptic area, and is secreted directly by the nerve endings into the pituitary portal circulation. After reaching the anterior pituitary gland, GnRH binds to the surface receptors of pituitary gonadotropin cells through the glycine group. Each gonadotropin cell has about 104 Gn receptors, usually as long as 10% GnRH receptors are bound to maximize Release Gn. The GnRH receptor complex selectively stimulates the release of LH and FSH from the anterior pituitary gonadotropin through the action of adenylate cyclase and calcium ions, and has a particularly strong effect on LH, thereby promoting the growth and development of follicles.

Gonadotropin-releasing hormone agonist (GnRH-a) is a highly effective analog of GnRH. At the 6th and 10th positions of the natural GnRH decapeptide, different amino acids and amides are substituted for the original amino acid structure. This change can make it It is not easy to be cleaved by endopeptidases in the body, so the stability is greatly enhanced, and the affinity to the GnRH receptor is also greatly increased. The biological titer of GnRH-a with different molecular structures is significantly different, which is 25 to 100 times that of natural GnRH. Commonly used preparations include ganarelin, leuprolide, triptorelin, buserelin, histamine and so on. Currently, triptorelin has the highest biological potency and has the widest clinical application.

GnRH-a has 10-20 times stronger receptor affinity and resistance to enzyme degradation than natural GnRH. In the early stage of administration, pituitary stimulation first appeared, which promoted pituitary Gn secretion and produced transient plasma gonadotropin peak flare-upreaction; and because GnRH-a has a higher affinity for GnRH receptors, it interacts with GnRH receptors. The body binding is more lasting. Most of the receptors are occupied and migrated into the cells during continuous administration, resulting in the down regulation of the pituitary GnRH receptor, the pulsed secretion rhythm disappears, Gn synthesis release is significantly reduced, and serum FSH and LH levels are significantly Decreased, showing a drug pituitary state. The secondary effect is that the follicles stop growing and developing, and the level of estrogen drops to early follicular or even menopausal levels. At this time, exogenous Gn is applied to induce the simultaneous development and maturation of multiple follicles for collection for in vitro fertilization.

Clinically, it is often used in combination with other hormones (such as gonadotrophins) in the IVF-embryo procedure to achieve the purpose of superovulation. The commonly used controlled ovulation promotion programs are:

(1) The long plan of the luteal phase. GnRHa was used in the mid-luteal phase of the previous cycle of pseudoovulation, and gonadotropin-stimulating ovulation was started after the pituitary down regulation was reached. After 6 to 8 days, the amount of Gn was appropriately adjusted according to follicular development.

(2) The long protocol at the beginning of the follicular phase. GnRH-a began to be used on the first and second days of the mid-menstrual period, and the pituitary descending regulation was achieved at about 14 days. Gn was started.

(3) Short plan. GnRH-a was used on the first or second day of menstruation, and Gn was the same length.

(4) Ultra-short plan: use GnRH-a only on the 2nd, 3rd, and 4th days of menstruation, and use Gn as above.

4. Gonadotropin-releasing hormone antagonists

GnRH-an and GnRH-a were discovered at the same time, but the structure was much more complicated than GnRH-a. It changed not only positions 6, 10, but also positions 1, 2, 3, and 5. There are changes. Because the amino acids at positions 1, 2, 3, 5, 6, and 10 are replaced by unnatural amino acids, GnRH-an has a higher affinity for the GnRH receptor, and competitively binds the GnRH receptor located in the pituitary gland, blocking Endogenous GnRH acts on this receptor to control endogenous Gn secretion, which is similar to the clinical effect produced by GnRH-a. But GnRH-an has the following advantages over GnRH-a:

(1) There is no initial excitation effect of GnRH-a, and no receptor desensitization effect will be generated after occupying the receptor site, and the effect of inhibiting the release of the gonad axis and sex hormones will be immediately exerted without the phenomenon of pituitary desensitization.

(2) It has a strong inhibitory effect on the female gonad axis. The dosage, time and side effects are small, and the method of use is simple, so it may become an ideal ovulation-promoting and ovarian protective drug. This provides favorable conditions for its application in controlling superovulation. In addition, because it does not stimulate endogenous Gn secretion, it can also be used to treat hormone-sensitive tumors of the reproductive system. Currently, clinically used drugs include cetrarelix and abelix.

The main clinical application of GnRH-an is in vitro fertilization-superovulation in embryo transfer in order to obtain high quality and large numbers of eggs. GnRH-an regimens are divided into single-dose or multi-dose regimens. Multi-dose regimen: gonadotropin-stimulating ovulation begins on the 3rd day of menstruation, and cetrorelix hydrochloride 0.25 mg is administered once a day until the day of hCG injection on the 6th day of ovulation or the diameter of the dominant follicle reaches 13-14mm. Single-dose regimen: gonadotropin-stimulating ovulation begins on the 3rd day of menstruation, cetrorelix hydrochloride 0.25 mg is used on the 6th day of ovulation, and if hCG is not injected on the 9th day of ovulation-promoting, we use HCl on the 10th day of ovulation-promoting Traricin 0.25 mg once daily until hCG injection day.

5. Aromatase inhibitors

Aromatase is a cytochrome P450 enzyme complex and a CYP19 gene product. It catalyzes the conversion of androstenedione and testosterone to estrone and estradiol, and is the rate-limiting enzyme for estrogen synthesis. Aromatase inhibitor

AIs) are divided into type I inhibitors (suicide or non-competitive) and type II inhibitors (competitive). Both types of inhibitors compete for binding to the active site. Commonly used drugs: Anastrozole, Letrozole, Exemestane. Exemestane is a type I inhibitor, and anastrozole and letrozole (LE) are type II inhibitors. At present, in the application of ovulation promotion, LE has been the most in-depth research and the most clinical application. There are two main mechanisms of LE's ovulation promotion:

(1) In the center, LE inhibits the aromatase activity, hinders the conversion of androgens to estrogen, and reduces the level of estrogen in the body, thereby eliminating the negative feedback effect of estrogen on the hypothalamus and pituitary and endogenous. Increased gonadotropin secretion promotes follicular development and ovulation.

(2) In the periphery, the increase of androgen concentration in the follicle can make the ovaries temporarily and reversibly polycystic ovary (PCO), which increases the sensitivity of the follicle to FSH / HMG. At the same time, androgens in the ovary can promote the development of early follicles. It has been found in primates that androgens can promote the proliferation of membrane cells and granulosa cells and inhibit their apoptosis, thereby increasing the number of pre-sinus follicles and sinusoidal follicles. This effect may be mainly achieved through the regulation of androgen receptors, because androgen receptors in granulosa cells in the early follicular phase are several times higher than mature follicles, and their gene expression levels are also higher. Androgen levels rise, insulin-like growth factor in follicles increases, and other endocrine and paracrine factors increase FSH to promote follicle recruitment and development. LE is a synthetic triphenyltriazole derivative, which is an oral, highly specific third-generation aromatase inhibitor. Many studies have suggested that LE ovulation-promoting can obtain similar ovulation effects as CC and is an effective ovulation-promoting drug. At the same time, it can overcome the adverse effects of CC on endometrium and cervical mucus, and can be used in patients with low response to CC.

6. Traditional Chinese medicine for promoting ovulation

The theory of traditional Chinese medicine believes that the kidney is the innate foundation, and Tibetan sperm is mainly responsible for reproduction. Kidney filling and essence and blood are the basis of follicular development and maturity; Chong Ren Qi and blood transfer, normal transformation of kidney yin and yang, are the conditions for ovulation; after ovulation, sufficient kidney essence and strong kidney yang are the keys to maintaining normal corpus luteum function. Insufficient kidney essence causes gasification weakness, blood loss, and even blood stasis. Therefore, the yin and yang of the kidney is imbalanced, and the function of Shengjinhua Qi and blood is insufficient, which can cause impotence or poor performance, cause ovulation disorders, and eventually cause menstrual disorders and infertility. Kidney deficiency is the basis and blood stasis is the standard. Therefore, tonifying the kidneys and regulating yin and yang is the basis for restoring ovulation.

Ovulation medication IV. Do not abuse ovulation medication

Ovulation drugs are mainly used to treat infertility patients with ovulation disorders by promoting ovulation. When prescribing this medicine to a patient, the doctor must prescribe the medicine strictly according to the patient's examination records before administering the medicine. It should be closely monitored during use, and the dose should be adjusted according to the patient's response to the drug. Multiple pregnancy is one of the side effects of this kind of drugs, which can cause serious complications such as miscarriage, premature delivery, pregnancy hypertension, intrauterine growth retardation, postpartum hemorrhage, etc., which can have adverse consequences for both mother and child. Another side effect of these drugs is the development of ovarian hyperstimulation syndrome. Ovulation-promoting drugs cause a large number of follicles to grow, the estrogen level in the body rises sharply, the double ovaries increase, and even torsion and rupture can cause ascites, pleural effusion, systemic edema, liver and kidney failure, and life-threatening severe cases ^[3] .

Now some women who can conceive normally also try to use ovulation-promoting drugs in order to have multiple births. Ovulation-promoting drugs can cause artificial multiple births, but they pose great risks to the health of mothers and infants. Because the complications of artificial multiple pregnancy are several times that of normal mothers, they are more prone to many complications such as anemia during pregnancy, hypertension, diabetes, polyhydramnios, placental abruption, placenta previa, and abnormal fetal position. Pain and danger are several times that of ordinary pregnant women, and severely overdrawn pregnant women are healthy. The more common complication is twin blood transfusion syndrome, a condition in which two fetuses in the womb snatch blood from each other, causing excessive blood in one fetus to cause heart failure, and dysplasia due to ischemia. Even fetal death. In addition, artificial twins are more likely to have an abnormal fetal position, stop fetal development, and have difficulty giving birth than singletons, and they are more likely to have preterm births ^[4] .

Ovulation drugs

At present, the pathogenesis of infertility caused by ovulation disorders is relatively clear. Western medicine promotes the effective period of follicular development is short and effective, but it is expensive and has many adverse reactions. Traditional Chinese medicine promotes follicular development with good curative effect, few adverse reactions, but slow effects, and many problems. For example, the current traditional Chinese medicine treatment is still based on clinical observation, the observation indicators and evaluation standards are also ambiguous, and the small sample size affects the clinical Efficacy evaluation and credibility; less research on drug action mechanism, obsolete observation indicators, etc. The existence of these problems has greatly restricted the research progress of traditional Chinese medicine in ovulation promotion. Therefore, it is the direction of future efforts to find a standardized model of Chinese medicine to promote ovulation and explain its treatment mechanism from the level of cell and molecular biology.