Commonly used drugs and protocols in infertility treatment

  (1) Clomiphene citrate (CC): CC is the most basic ovulation-promoting drug. It has anti-estrogenic effects and its main site of action is in the hypothalamus, competing with endogenous estrogen for receptors, making the hypothalamus sensitive to the positive feedback effect of estrogen, prompting the hypothalamus to release GnRH, stimulating the pituitary gland to secrete FSH and LH, and promoting follicular development and ovulation. Indications are: hypothalamic amenorrhea, amenorrhea due to contraceptive use, PCOS, ovulation disorder due to hyperprolactinemia. The basic use is to take CC50mg-100mg orally daily for 5 days starting on day 5 of the menstrual cycle. Other drugs include letrozole and tamoxifen.  Combination regimen: ① E+CC+hCG: where E is commonly used as estradiol valerate (e.g., Glaxo®) 1mg/d. This regimen is used for patients with primary amenorrhea, secondary amenorrhea, and scanty menstruation.  ② CC+E+hCG: This regimen is used for patients with scanty menstruation, prolonged follicular phase, and anovulation.  (3) CC+HMG+hCG (2) Gonadotropins: Commonly used gonadotropin preparations include menopausal gonadotropins (HMG), purified FSH, high-purity FSH (FSH-HP), genetically recombinant FSH (r-FSH), and hCG. The indications are amenorrhea or ovulation disorders due to hypothalamic-pituitary dysfunction, ovulation disorders where CC therapy is ineffective, superovulation in assisted reproductive technology, and unexplained infertility. Basic dosing: Start on day 3-5 of the menstrual cycle or withdrawal bleeding and inject 37.5 IU-150 IU of HMG or FSH intramuscularly daily.  Combination regimen: ① CC+HMG+hCG ② HMG/FSH+hCG ③ FSH+HMG+hCG (3) Gonadotropin-releasing hormone and its analogues: GnRH is also known as LHRH. GnRH is a peptide hormone secreted by the hypothalamus, which is released in a pulsatile manner, once every 90-120 minutes, to promote the secretion of FSH and LH from the pituitary gland. GnRH has been synthesized and is chemically known as Gonodorelin. Gonadotropin-releasing hormone analog (GnRH-a) is a highly potent analogue of GnRH, which is 10-20 times more potent than GnRH. It promotes pituitary gonadotropin secretion at the beginning of administration and causes pituitary gonadotropin secretion to be down-regulated by continuous administration, thus inhibiting pituitary gonadotropin secretion and thus treating some estrogen-dependent diseases. Buserelin, Histerelin, and Leuprorelin are commonly used. They can be administered nasally, subcutaneously or intravenously. The indications for GnRH therapy are amenorrhea or ovulation disorders due to hypothalamic dysfunction.  GnRH pulsed therapy: pulsed injection of gonadotropin-releasing hormone.  GnRH induces ovulation: After HMG or CC promotes follicular maturation, GnRH can be given to stimulate the pituitary gland to secrete LH and FSH to induce ovulation.  (iii) GnRH-a can be used in the treatment of estrogen-dependent disorders, in superovulation protocols in assisted reproductive technologies, and also in combination with PCOS treatment.  (1) Amenorrhea: Patients with amenorrhea should first have their degree and etiology defined. Patients with low estrogenic amenorrhea should be treated with oral estradiol valerate for three months by taking 1 to 2 mg of estradiol valerate (e.g., Glaxo®) orally daily for 21 days, followed by progesterone daily for 10 days starting on day 12. Repeat on day 5 of withdrawal bleeding for a total of 3 consecutive cycles. It increases blood estradiol concentrations to late follicular levels in women of childbearing age and acts effectively on target organs. When ovarian sensitivity to gonadotropins is restored, ovulation treatment is then administered. For hypothalamic amenorrhea and ovulatory disorders, clomiphene is the preferred and simplest treatment option, as well as GnRH pulse therapy. In hypothalamic-pituitary dysfunction, ovulation can be promoted with HMG or pure FSH.  (2) Hypo-PRL: Hypo-PRL can lead to anovulation and luteal insufficiency. Bromocriptine is an effective drug.  (3) PCOS: The endocrine profile of PCOS patients is characterized by elevated LH and T in the blood. Clomiphene is a safe and effective method to promote ovulation, but gonadotropins can be used if it is not effective. Patients with PCOS have excessive androgens that affect follicular development, and can be better treated with contraceptives, flutamide, adrenocorticotropic hormone or progestin to suppress androgen secretion before ovulation.  (4) Luteinized unruptured follicle syndrome (LUFS): there are 2 treatment methods: ① Promote ovulation: when the follicles reach 18-24 mm in diameter and are monitored by ultrasound, inject 5000-10,000 IU of hCG intramuscularly, or add 150 IU of HMG or 150 IU of FSH along with the hCG.  (2) Promote follicular development: For follicles with luteinization before reaching maturity, CC + hCG or HMG/FSH + hCG can be used to promote ovulation.  (5) Luteinizing insufficiency: Treatment includes: ① Supplementing luteal function: Exogenous progesterone should be given to support the development of endometrium to facilitate the implantation and development of fertilized eggs.  (2) Promote luteal function: hCG can promote and maintain luteal function, inject 1000 IU of hCG daily or 2000 IU every other day after ovulation.  (3) Promotion of follicular development and luteal function: Ovulation promotion therapy is effective, and CC + E + hCG or HMG/FSH + hCG regimens can be used.  (6) Hyperandrogenemia: for hyperandrogenemia of adrenal origin, suppression with adrenocorticotropic hormone, such as oral dexamethasone 0.375 mg daily for 22 days starting on day 2 of the menstrual cycle, with additional ovulation treatment. Patients with hyperandrogenemia of ovarian origin, such as PCOS, can be counteracted with progestational agents, such as the short-acting oral contraceptives DAL-35® (ethinylestradiol and cyproterone acetate), for 1-3 cycles, and then start ovulation treatment after the androgens have decreased to normal levels. Flutamide can be used to treat hyperandrogenemia of adrenal or ovarian origin.