Controlled Ovarian Hyperstimulation The goal of gonadotropin stimulation for ART is the synchronous growth of dominant follicles in quantities greater than that associated with non-ART therapy. FSH is the key hormone in this regard (111). Gonadotropin preparations are described in the “Ovulatory Factor” section, while dosing and the relevance of baseline ovarian cysts are described in the “Unexplained Infertility” section. ART pregnancy outcomes are not affected by the source of FSH, the delivery system, or the route of administration (156). In one recent report, women who were predicted to be normal responders using 225 to 300 IU of FSH required 11 days of stimulation, had 11 to 13 follicles 15 mm or larger on the day of hCG trigger, had a peak E2 level of approximately 2,100 pg/mL, and had 10 to 11 oocytes retrieved, of which 82% to 83% were mature (111). Most investigators suggest that the optimal number of retrieved oocytes in a given cycle is between 5 and 15, and the optimal level of estradiol at the time of hCG administration is between 70 and 140 pg/mL per oocyte or follicle (306,329). It should be noted that the utility of estradiol monitoring during ART is controversial, and that ultrasound monitoring alone may be adequate to maximize pregnancy and live birth rates (309). Cycle cancellation in normal responders occurs in up to 6% of the cycles because of inadequate response and 1.5% of cycles for excessive response (111). Cycle cancellation increases with older age and decreased ovarian reserve, but is reportedly decreased by 2% for every additional 100 IU gonadotropins used (328). There appears to be no benefit of exceeding a total daily gonadotropin dose of 450 IU in any patient (301).
Follicle-Stimulating Hormone versus Human Menopausal Gonadotropin Higher androgen and lower progesterone levels on the day of hCG trigger are observed when HMG is used for stimulation rather than FSH alone, indicating a more favorable endocrine profile with HMG (334). Concern has been raised that exogenous LH might be needed to address the sudden decrease in endogenous LH that is associated with GnRH antagonist use and the possible excess endogenous LH suppression in long GnRH agonist protocols (326). However, there is no consensus as to whether the addition of LH to exogenous FSH improves pregnancy and live birth outcomes in women with normal hypothalamic function (156,335,336).
Less Aggressive Stimulation Although it reduces cancellation rates, each additional 100 IU of gonadotropins is correspondingly associated with a 2% lower rate of clinical pregnancy and live birth (328). This seems to support the findings of premature luteinization and lower pregnancy rates when more aggressive FSH stimulation protocols are used (320). When comparing normal responders using a ﬂexible antagonist protocol and a fixed FSH dose of 150 IU (mild) to those using conventional FSH doses, implantation rates were maximized when a median of 5 oocytes were retrieved in the mild stimulation group, while 10 oocytes were necessary in the conventional dose group. Outcomes were compromised when more than eight oocytes were obtained in the mild group, and only the high dose group experienced poorer outcomes with low oocyte yield. Pregnancy rates seem to level off or decrease when stimulation is pushed beyond a certain threshold, but this threshold is unknown (329).