Progesterone Gel or Injection for Luteal Phase Support in IVF

Peter Kovacs, MD, PhD


January 31, 2011

Crinone Vaginal Gel Is Equally Effective and Better Tolerated Than Intramuscular Progesterone for Luteal Phase Support in In Vitro Fertilization-Embryo Transfer Cycles: A Prospective Randomized Study

Yanushpolsky E, Hurwitz S, Greenberg L, Racowsky C,
Hornstein M
Fertil Steril. 2010;94:2596-2599


A healthy embryo and an adequately built up endometrium are needed for successful implantation. The endometrium undergoes cyclic changes. Following menstruation, when the functional layer of the endometrium is shed, intense proliferation is induced by the increased amount of estrogen produced by the follicles. As a result of estradiol exposure, a 10- to 15-mm thick endometrium develops. Following ovulation, progesterone produced by the corpus luteum induces well-characterized changes in the endometrium.[1] These secretory changes prepare the endometrium for implantation in case a healthy blastocyst reaches the uterine cavity. When progesterone production is inadequate, however, luteal phase insufficiency may develop. The intrauterine environment may not become receptive for the blastocyst, and therefore implantation is hindered.

The situation is the same in medically assisted cycles. When medications are used to promote follicle growth, the endometrium undergoes the same proliferative-secretory cycle. The medications and any further procedures (such as egg retrieval) will often result in luteal phase deficiency; therefore, progesterone support in the second half of the cycle is needed to allow implantation. This randomized study compared Crinone® vaginal gel (a progesterone gel) and progesterone injection for luteal support during in vitro fertilization (IVF) cycles.


Yanushpolsky and colleagues randomly assigned 468 patients to receive 50 mg progesterone in oil given by intramuscular injection or 90 mg progesterone gel for luteal support during IVF treatments. Patients under the age of 40 years with baseline follicle-stimulating hormone (FSH) levels below 15 IU/L who were having stimulation with the luteal long protocol (150-600 IU recombinant FSH) were eligible to participate. Of the initial group of eligible women, 407 completed the study. Baseline characteristics were well matched. Ongoing pregnancy rates were comparable (45% gel vs 42% injection). Pregnancy loss rates (spontaneous abortion, biochemical pregnancy, and ectopic pregnancy) were similar as well (32% gel vs 32% injection). Satisfaction with the type of luteal support was measured on a scale of 1 (lowest rating) through 5 (highest rating). Women who were assigned to the use of the vaginal gel were significantly more satisfied with the product than those who used the injections (4.4 gel vs 2.8 injection).


Regardless of the endocrine findings for spontaneous cycles, patients who require assisted reproduction need luteal support during IVF because the treatment itself leads to luteal insufficiency. This is explained to some extent by the use of drugs for downregulation (GnRH agonist or antagonist), partly by the suppressive effect of the supraphysiologic estradiol levels reached during stimulation, and partly by the removal of the granulosa cell mass (that eventually would luteinize) during retrieval.

Two general types of luteal support are available. Human chorionic gonadotropin can be given to maintain corpus luteum function. This is an effective method, but it is associated with an increased risk for ovarian hyperstimulation syndrome (OHSS). In patients who respond well to stimulation, this is not an option because all measures that can reduce the risk for OHSS must be used.

Alternatively, the "product" of the corpus luteum -- progesterone -- can be used. Progesterone can be administered via 3 different routes:

  1. Oral agent. When taken by the oral route, following absorption, progesterone is passed through the liver where most of it is metabolized. If very high doses are not taken, it will not be effective. However, when high-dose progesterone is used, the metabolic products are associated with significant sedative side effects, and therefore is not well tolerated.

  2. Intramuscular injection. Intramuscular administration is highly effective but requires daily injections that can be associated with injection site reactions. Injections are also painful; therefore, use of this route introduces an unnecessary stress factor into a patient's treatment regimen that may be counterproductive.

  3. Vaginal product. When administered vaginally, progesterone is absorbed through the uterus where high tissue levels of progesterone can be achieved. It reaches the systemic circulation and the liver only after passing through the uterus. Vaginal products have been shown to be as effective as intramuscular agents in previous studies.[2,3]

To date, this study by Yanushpolsky and colleagues is the largest study comparing vaginal progesterone gel with intramuscular progesterone injection. The study had adequate power and a sound design to compare the 2 products. Clinically, they were similarly effective; pregnancy and pregnancy loss rates were similar. The vaginal product, however, was much better tolerated. Using progesterone vaginally eliminates a stress factor from the treatment regimen and makes it more patient-friendly without compromising its efficacy. Serum levels cannot be monitored accurately because serum and tissue levels of progesterone could differ significantly. Therefore, when bleeding occurs it may be more difficult to determine whether this indicates a problem with the pregnancy itself or is related to the luteal support. Despite this disadvantage, the vaginal route of administration should still be the first choice because outcomes are not compromised by this method and it is well tolerated.



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