What are the commonly used ovulation drugs?

Ovulation drugs are mainly used to help some patients with ovulatory infertility to promote ovulation, thereby achieving the effect of pregnancy. The side effect of using ovulation drugs is that there are generally more multiple births, which increases the risk of miscarriage, premature birth, gestational hypertension, postpartum hemorrhage, etc., which will have very bad consequences for both adults and children.

1. Clomiphene

Clomiphene (CC), also known as clomiphene citrate, is a non-steroidal compound with a chemical structure similar to chlorfenapyr. It has moderate anti-estrogen and weak estrogenic effects. CC can compete with endogenous estrogen for receptors with a stronger affinity. By competitively binding to estrogen receptors in the hypothalamus, it makes target cells insensitive to estrogen, relieves the negative feedback effect of estrogen on the hypothalamus, increases the frequency of hypothalamic gonadotropin-releasing hormone (GnRH) release, and increases the release of FSH and LH from the pituitary gland. FSH promotes the maturation of follicles. The rise in estradiol (E2) levels before ovulation causes a positive feedback effect, which further increases the frequency of central GnRH release. The pituitary gland releases more FSH and LH, especially LH, forming an LH peak and inducing ovulation.

The clinical effect of CC ovulation induction has been widely studied and reported. It is suitable for infertile women whose hypothalamic-pituitary-ovarian gonadal function is weakened or uncoordinated to a certain extent and whose follicular development is impaired. Hypogonadism caused by hypothalamic-pituitary failure is its best indication. Its dosage and usage should be individualized and adjusted appropriately with changes in the function of the gonad axis. In general, the ovulation rate is 70%~90%, the pregnancy rate is 30%~40%, the pregnancy rate with ovulation cycle is 20%~25%, and the abortion rate is 20%, which is slightly higher than the abortion rate of natural pregnancy (12%~15%).

2. Gonadotropin

Human gonadotropin (Gn) mainly includes FSH and LH secreted by the pituitary gland and human chorionic gonadotropin (HCG) secreted by the placenta, all of which are glycoprotein hormones. Gn has an enhancing effect on the recruitment and growth of follicles during folliculogenesis, stimulating the growth and maturation of follicles. FSH promotes the activity of aromatase in granulosa cells, converts androgens into estrogens, increases the level of estrogen and promotes the proliferation of the endometrium, and can be used to induce ovulation or superovulation. FSH and LH work synergistically to stimulate the proliferation and differentiation of various cells in the follicles, and stimulate the growth and development of the follicles. LH mainly stimulates theca cells to produce androgens, which are the substrates of aromatase. Therefore, LH plays a role in estrogen production in collaboration with FSH, and promotes the final maturation of follicles and oocytes, triggers ovulation, promotes the formation of the corpus luteum, and maintains the function of the corpus luteum. The products currently in clinical use include HCG extracted from the urine of pregnant women, human menopausal gonadotropin (HMG) extracted from the urine of menopausal women, human follicle-stimulating hormone (u-FSH) extracted and purified from urine, highly purified human follicle-stimulating hormone (u-FSHHP), and recombinant FSH (rFSH) and LH (r-LH) produced by genetic recombination engineering technology.

The main ones currently used in clinical practice are HCG and HMG. HCG can promote and maintain the function of the corpus luteum, enable the corpus luteum to synthesize progesterone, promote the formation and maturation of follicles, and simulate the physiological peak of luteinizing hormone to induce ovulation; HMG has the effect of FSH, promoting the development and maturation of follicles in the ovaries and causing 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 acids in its structure are arranged as follows: glutamic acid-glutamic acid-color-silk-casein-leucine-crystal-prospermuminosae-glycine. Endogenous GnRH is synthesized in the GnRH cells of the arcuate nucleus and preoptic area of ​​the medial basal hypothalamus and is secreted directly into the pituitary portal circulation by nerve endings in a pulsed manner. After reaching the anterior pituitary, GnRH binds to the surface receptors of pituitary gonadotropin cells through the glycine group. Each gonadotropin cell has about 104 Gn receptors. Usually, Gn can be released to the maximum extent as long as 10% of the GnRH receptors are bound. The GnRH receptor complex selectively stimulates the anterior pituitary gonadotropins to release LH and FSH through the action of adenylate cyclase and calcium ions, with 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. It replaces the original amino acids at the 6th and 10th positions of the natural GnRH decapeptide with different amino acids and amides. This change makes it less likely to be cleaved by endopeptidases in the body, thereby greatly enhancing its stability and greatly increasing its affinity for the GnRH receptor. The biological potency of GnRH-a with different molecular structures varies significantly, which is 25 to 100 times that of natural GnRH. Commonly used preparations include gonadorelin, leuprorelin, triptorelin, buserelin, histrelin, etc. Currently, triptorelin has the highest biological efficacy and is the most widely used in clinical practice.

GnRH-a has a receptor affinity 10 to 20 times stronger than that of natural GnRH and is able to resist enzymatic degradation. In the initial stage of drug administration, pituitary stimulation occurs first, promoting pituitary Gn secretion and producing a transient plasma gonadotropin peak, i.e., a flare-up reaction. Also, because GnRH-a has a higher affinity for GnRH receptors and binds to GnRH receptors for a longer period of time, most of the receptors are occupied and internalized into the cells when the drug is continuously administered, causing pituitary GnRH receptor downregulation, disappearance of the pulsed secretion rhythm, a significant reduction in Gn synthesis and release, and a significant decrease in serum FSH and LH levels, resulting in a drug-induced hypophysitis. The secondary effect is that follicles stop growing and developing, and estrogen levels drop to early follicular or even menopausal levels. At this time, exogenous Gn is applied to induce the synchronous development and maturation of multiple follicles so that they can be collected for in vitro fertilization.

Clinically, it is often used in combination with other hormones (such as gonadotropin) in in vitro fertilization-embryo transfer procedures to achieve the purpose of super ovulation. The commonly used controlled ovulation induction regimens are:

(1) Long regimen starting in the luteal phase. GnRHa is used in the mid-luteal phase of the cycle before superovulation, and gonadotropin-induced ovulation is started after pituitary downregulation is achieved. After the 6th to 8th day, the dosage of Gn should be adjusted appropriately according to the development of follicles.

(2) Long protocol starting in the follicular phase. GnRH-a is started on the 1st or 2nd day of the mid-menstrual period. Pituitary downregulation can be achieved around 14 days, and Gn can be started.

(3)Short plan. Start using GnRH-a on the 1st to 2nd day of menstruation, and use the same length regimen for Gn.

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

4. Gonadotropin-releasing hormone antagonists

Gonadotropin-releasing hormone antagonist (GnRH-an) was discovered at the same time as GnRH-a, but its structure is much more complex than that of GnRH-a. It not only changes the 6th and 10th positions, but also has changes at the 1st, 2nd, 3rd, and 5th positions. Because the amino acids at positions 1, 2, 3, 5, 6, and 10 are replaced by non-natural amino acids, GnRH-an has a higher affinity for the GnRH receptor, competitively binds to the GnRH receptor located in the pituitary gland, and blocks the action of endogenous GnRH on the receptor to control the secretion of endogenous Gn, 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 stimulating effect of GnRH-a at the initial stage of medication. After occupying the receptor site, no receptor desensitization effect is produced. It can immediately exert the effect of inhibiting the gonadal axis and the release of sex hormones without causing pituitary desensitization.

(2) It has a strong inhibitory effect on the female gonadal axis. The dosage, duration of use and side effects are relatively small and the method of use is simple. Therefore, it may become a more ideal drug for ovulation induction and ovarian protection. This provides advantages for its application in controlling superovulation. In addition, since it reduces endogenous Gn secretion without stimulation, it can also be used to treat hormone-sensitive tumors of the reproductive system. Currently, the commonly used drugs in clinical practice include cetrorelix and abirelix.

The main clinical application of GnRH-an is superovulation in in vitro fertilization-embryo transfer to obtain high-quality and large quantities of eggs. GnRH-an regimens are divided into single-dose or multiple-dose regimens. Multi-dose regimen: Gonadotropin-induced ovulation begins on the third day of menstruation, and cetrorelix hydrochloride 0.25 mg is used once a day on the sixth day of ovulation or when the dominant follicle reaches 13-14 mm in diameter until the day of hCG injection. Single-dose regimen: Gonadotropin-induced ovulation begins on the third day of menstruation, and 0.25 mg of cetrorelix hydrochloride is used on the sixth day of ovulation. If hCG is not injected on the ninth day of ovulation, 0.25 mg of cetrorelix hydrochloride is used from the tenth day of ovulation, once a day until the day of hCG injection.

5. Aromatase inhibitors

Aromatase is a cytochrome P450 enzyme complex and a product of the CYP19 gene. It catalyzes the conversion of androstenedione and testosterone into estrone and estradiol and is the rate-limiting enzyme in estrogen synthesis. Aromatase inhibitors (

AIs are divided into type I inhibitors (suicide or noncompetitive) 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. Currently, LE has been the most intensively studied and clinically used in ovulation induction applications. The mechanism of LE ovulation induction is mainly in two aspects:

(1) In the central nervous system, LE inhibits the activity of aromatase, hinders the conversion of androgens to estrogens, and reduces the level of estrogen in the body, thereby eliminating the negative feedback effect of estrogen on the hypothalamus and pituitary gland, increasing the secretion of endogenous gonadotropin, and promoting the development of follicles and ovulation.

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

6. Chinese medicine for promoting ovulation

According to traditional Chinese medicine theory, the kidney is the foundation of one’s constitution, stores essence and controls reproduction. Fullness of kidney qi and abundant essence and blood are the basis for the development and maturation of follicles; the regulation of Chong and Ren qi and blood and the normal transformation of kidney yin and yang are the conditions for ovulation; sufficient kidney essence and abundant kidney yang after ovulation are the key to maintaining normal corpus luteum function. If the kidney essence is insufficient, the qi will be unable to transform, the blood will not flow smoothly, and even blood stasis will occur. Therefore, the imbalance of yin and yang in the kidney and the insufficient function of producing body fluid, transforming qi and blood can lead to malnutrition or obstruction of the Chong and Ren meridians, causing ovulation disorders and ultimately leading to menstrual disorders and infertility. Kidney deficiency is the root cause and blood stasis is the symptom, so tonifying the kidney and regulating yin and yang are the fundamentals to restoring ovulation.