Clomiphene effectiveness is decreased by obesity, increased age, and hyperandrogenic states (142,148,149). Side effects of clomiphene citrate include vasomotor ﬂushes, mood swings, breast tenderness, pelvic discomfort, and nausea. In a minority of individuals, the antiestrogenic effects of clomiphene citrate at the level of the endometrium or the cervix may have adverse effects on fertility. In the presence of visual abnormalities, clomiphene citrate should be discontinued promptly. Multiple gestation rates with clomiphene citrate are approximately 8%, most of which are twins (136). Treatment should be limited to 6 ovulatory cycles or 12 total cycles (141,150,151).
Clomiphene Citrate Dosing The drug is supplied in 50 mg tablets; the usual starting dose is 50 mg per day, but patients who are very sensitive may respond to 12.5 to 25 mg per day. Therapy is typically begun within the first 5 days after the onset of a spontaneous or progesterone-induced menses and is continued for 5 days (i.e., treatment on days 2 to 6, 3 to 7, or 5 to 9 of the menstrual cycle) (136). It has been reported to be effective when started the day following progesterone withdrawal therapy, without waiting for menses (152). If ovulation does not occur at the initial dosage of clomiphene citrate, the dosage is increased in each subsequent cycle by 50 mg per day. Seventy-four percent of women will ovulate with 100 mg per day, the maximum dose approved by the U.S. Food and Drug Administration (153). However, some patients need higher doses, which have been safely given up to 250 mg per day (136). A novel stair-step method has been proposed, which increases the dose within a single cycle without intervening menses if there was no follicular response documented by ultrasound 4 to 5 days after the last pill (154). However, this particular protocol raises concern for unknown endometrial and embryonic effects (155).
Ovulation Monitoring during Clomiphene Citrate Therapy If preovulation monitoring is not performed, patients should be instructed to have intercourse every 2 to 3 days following the last day of therapy and check a serum progesterone weekly for 5 weeks before inducing a withdrawal bleed or increasing the clomiphene citrate dose (142). Although no clear advantage has been demonstrated for any ovulation monitoring technique, regular contact should be maintained with patients to review response to therapy. The urinary LH surge may be detected 5 to 12 days after treatment is completed. When clomiphene is given cycle days 5 to 9, the surge typically occurs on cycle day 16 or 17 and can be confirmed by midluteal serum progesterone testing 7 days later. With ultrasound monitoring, treatment should be withheld if large cysts are seen on baseline testing. Following clomiphene, follicles typically reach a preovulatory diameter of 19 to 25 mm by ultrasound, but may be as large as 30 mm (136,137). A combination of LH testing and ultrasound can be used, with LH kits starting when the largest ultrasound-measured follicle reaches 14 mm in diameter (131).