Superovulation (Controlled Ovarian Hyperstimulation) Unlike ovulation induction, in which the goal is to stimulate the release of a single oocyte in a women who was not previously ovulating, the explicit goal of superovulation (for non-ART or ART purposes) is to cause more than one egg to be ovulated, thereby increasing the probability of conception in women with unexplained infertility (136). In most superovulation protocols, a baseline scan is performed on day 2 of the menstrual cycle to assess antral follicle count and the presence or absence of ovarian cysts. Baseline estrogen and progesterone levels are typically obtained on this day (301). Starting daily doses in superovulation cycles are higher for both clomiphene (100 mg for 5 days) and gonadotropins (150 to 300 IU daily) than those used for ovulation induction (111,301,302). Superovulation with clomiphene is otherwise conducted as described above for ovulation induction. When gonadotropins are used for normal responders with unexplained infertility, FSH doses of 225 IU and 300 IU lead to similar outcomes with IVF (111). The maximal gonadotropin dosage is typically 450 IU per day because higher dosages do not increase ovarian response (301). In most superovulation protocols, gonadotropins are started on day 2 or 3 of menses (301–303). The starting dose of gonadotropins is maintained each day until cycle day 6 or 7 (stimulation day 4 or 5), when the serum estradiol level and transvaginal ultrasound are first measured to document ovarian response (111,302,303). Gonadotropin dosage is increased by 50 to 100 IU per day every 2 to 4 days until a response is evident (304). Estradiol levels typically double every 48 hours, with follicle growth of 1 to 2 mm daily after a 10 mm diameter is reached (305). Triggering of ovulation typically occurs when at least two follicles have reached an average diameter 17 to 18 mm and the endometrial thickness is 8 mm or more (111,302,303,306–308). For non-ART cycles, cancellation should be strongly considered for E2 levels 1,000 to 2,500 pg/mL, for three or more follicles 16 mm or more, or for two or more follicles 16 mm or more plus two or more follicles 14 mm or more (141). Ultrasound monitoring of IVF cycles without estradiol levels can be considered (309).
Treatment Outcomes It should be noted that pregnancy rates in unexplained infertility patients vary widely among studies, even when the same treatments are used, perhaps as a result of heterogeneity in treatment protocols and patient age. Interpretation of data on the use of clomiphene in patients with unexplained infertility is particularly difficult because the studies are heterogeneous and their results conﬂicting (150,151). One meta-analysis of 1,159 participants with unexplained infertility involving seven randomized controlled trials of clomiphene citrate with and without IUI indicated no improvement in pregnancy or live birth rates when compared to no treatment or placebo (151). Still, oral therapies continue to be used, and clomiphene and letrozole have recently been shown to have comparable efficacy when combined with IUI for treating unexplained infertility, with pregnancy rates approximately 18% per cycle (310). Combined therapy with gonadotropins and IUI is more likely to result in pregnancy