HCG Injection After Ovulation Induction With Clomiphene Citrate

Question

I have a patient undergoing ovulation induction with clomiphene citrate. What are your thoughts about subsequent HCG injection for egg release? What is the recommended dosage and timing in the cycle?

C. Joshi, MD

Response from Peter Kovacs, MD, PhD

Several agents are used to induce follicular growth. Selective estrogen receptor modulators (clomiphene citrate, tamoxifen), gonadotropins (human menopausal gonadotropin, recombinant preparations), and aromatase inhibitors are all available for controlled ovarian stimulation. They can be used to induce follicular growth when it is absent (oligo-ovulation, anovulation) or to induce the growth of multiple follicles (eg, mild male factor infertility, endometriosis, unexplained infertility). The appropriate drug is selected on the basis of the indication, age of the patient, response to previous treatment, potential contraindications to certain drugs, and expense.

Clomiphene citrate is usually the first choice when follicular development is irregular, for a younger patient, or when a less expensive preparation is required. Initially, the daily dose is 50 mg and can be increased as necessary. Generally, there is no need for doses exceeding 150 mg daily. In addition, higher doses exert a negative effect on the endometrium, so avoiding higher doses is recommended. Treatment is initiated on day 3 or 5 of the cycle and continues for 5 days. In the case of oligo-ovulation/anovulation, the goal is to induce monofollicular growth; for other indications, the simultaneous growth of 2 to 4 follicles is desired.

Follicular growth is monitored by ultrasound. The first ultrasound is scheduled on day 10 and then every 2-3 days if necessary. Spontaneous ovulation can be expected when the lead follicles reach 18-20 mm. Alternatively, ovulation can be induced with human chorionic gonadotropin (HCG) or gonadotropin-releasing hormone agonist (GnRHa). Follicular growth and ovulation following clomiphene citrate administration can be observed in up to 85% of women with ovulatory dysfunction. Cumulative pregnancy rates are lower (40% to 50%), however, probably as a result of the adverse endometrial effects.

Ovulation occurs as a response to sustained high estradiol levels. Clomiphene citrate may interfere with the normal ovulatory process because of its antiestrogenic properties, although, in most cycles, ovulation will occur. Further ultrasound studies or urinary luteinizing hormone (LH) tests can aid detection of ovulation.

Once the follicle is ruptured and the oocyte is released, it has 24-36 hours for fertilization. Therefore, the timing of oocyte release is very important. HCG has similar activity to LH and binds to its receptor. It is capable of inducing luteinization and ovulation. Ovulation occurs 38 to 40 hours after a single HCG injection. There are urinary and recombinant HCG preparations. Urinary preparations are given as a single dose of 5000-10,000 IU in the form of an intramuscular injection. Recombinant HCG is given as a single dose of 250 mcg in the form of a subcutaneous injection. Recombinant HCG has similar pharmacokinetics as the urinary formulation; therefore, ovulation is expected following a similar time interval. The use of HCG will allow better timing of sexual intercourse or intrauterine insemination. In addition, as HCG has a half-life of about 35 hours, it will support the initial part of the luteal phase.

As ovulation following clomiphene citrate stimulation will not occur in every cycle and the timing of egg release is very important, the use of HCG to induce ovulation is justified. This is especially true for those patients who failed to conceive during previous clomiphene cycles. In addition, HCG will provide further luteal phase support.

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