Evaluation of a Long Versus Short Clomid Protocol for Controlled Ovarian Stimulation

Clomiphene citrate (Clomid) is often used for assisted reproductive technologies and may be used to augment ovarian stimulation with exogenous gonadotropins by stimulating pituitary follicle-stimulating hormone (FSH) release in addition. The mechanism of action of Clomid is antagonism at the estrogen receptor, and this stimulates FSH release from the pituitary. The typical Clomid-based protocol has involved clomid only given for the first five days of stimulation to allow for endometrial development later in the cycle for a fresh embryo transfer following the oocyte retrieval. This protocol involves the addition of a GnRH antagonist medication later in the cycle to prevent premature ovulation. Recent national trends in IVF, however, have moved towards frozen embryo transfers and use of preimplantation genetic testing, which obviates any concerns regarding the endometrium. Recent experience in our clinic has suggested that Clomid may also prevent premature ovulation by antagonizing the positive feedback that is responsible for the luteinizing hormone (LH) surge and ovulation. Given in this manner, Clomid can be given throughout the duration of an ovarian stimulation cycle, achieve higher FSH levels and degree of ovarian stimulation in patients with diminished ovarian reserve, and obviate the need for GnRH antagonist medication (another expensive subcutaneous injection). The objective of this study is to compare a "long Clomid protocol" (i.e. using Clomid throughout the entire duration of the IVF cycle) as compared to the typical 5-day clomid protocol. The investigators hypothesize that the long Clomid protocol will be non-inferior to the typical five-day course and obviate the need for GnRH antagonist by preventing premature ovulation. Patients with diminished ovarian reserve and anticipated poor response to ovarian stimulation will be randomized to the long Clomid protocol vs. a 5-day Clomid with GnRH antagonist protocol. The primary outcome will be oocyte yield. Secondary outcome will be premature ovulation, embryo development, and pregnancy outcomes.

Inclusion criteria

• Undergoing IVF
• Must meet POSEIDON criteria based on clinic evaluation
• Female partner: Antral follicle count of 2 or more and age <45 at time of stimulation start
• Male partner/sperm source: Cannot be azoospermic
• Planning freeze-all cycle (regardless of blastocyst or cleavage stage culture) or fresh transfer if randomized to short Clomid group
• Planning 36-hour trigger window

Exclusion criteria

• Normal ovarian reserve or good response
• Allergy or adverse reaction to Clomid
• Minimal stimulation protocols
• History of prior premature ovulation