An Option for Luteal Phase Support in In Vitro Fertilization

Subcutaneous Progesterone Versus Vaginal Progesterone Gel for Luteal Phase Support in In Vitro Fertilization: A Noninferiority Randomized Controlled Study

Lockwood G, Griesinger G, Cometti B; 13 European Centers
Fertil Steril. 2014;101:112-119

The Study

A normal menstrual cycle has 3 phases: menstruation, the follicular phase, and the luteal phase. In the follicular phase, the emerging follicle produces increasing amount of estradiol that leads to the proliferative build-up of the endometrium. This is in preparation for implantation. At ovulation (mid-cycle), the follicle ruptures and the egg is released. In conception cycles, the egg will be fertilized and the embryo will migrate to the endometrium, where it will implant.

After ovulation, the follicle turns into the corpus luteum. The main secretory product of the corpus luteum is progesterone, which induces secretory endometrial changes; it is these qualitative changes that will make the endometrium receptive to the blastocyst.^[1]

The corpus luteum maintains its activity for 14 days. If the embryo fails to implant and human chorionic gonadotropin (hCG) is not secreted, its activity declines and menstruation will follow. If the embryo implants, hCG will be secreted to rescue the corpus luteum. The normal development of pregnancy depends on proper corpus luteum activity up until the luteoplacental shift (7-10 weeks' gestation), when the placenta takes over endocrine control of the gestation.^[2]

In vitro fertilization (IVF) cannot be considered a physiologic process. In most cases, multiple follicles grow simultaneously and secrete supraphysiologic amount of estradiol. Down-regulation using gonadotropin-releasing hormone (GnRH) agonist or antagonist is used to avoid premature luteinization. At the time of "ovulation," a transvaginal egg collection procedure is done that removes significant amount of the granulosa cell mass as well. These events typically induce luteal phase insufficiency, and without proper luteal support, pregnancy rates are lower and miscarriage rates are higher.

The luteal phase can be supported by repeated doses of hCG or progesterone. Progesterone is available as an oral, transvaginal, or intramuscular product.

A new water-soluble progesterone preparation was developed that can be administered as a subcutaneous injection. This study compared the efficacy and tolerability of this preparation with that of one of the vaginal products already on the market.

This open-label, randomized, controlled trial was performed in 13 centers and involved 683 participants. Infertile patients undergoing IVF or intracytoplasmic sperm injection who had at least 3 eggs retrieved were randomly assigned to receive either 25 mg progesterone by subcutaneous injection or 90 mg vaginal progesterone gel (Crinone®) from the day of retrieval. Treatment was continued at least up until the pregnancy test, and in case of a positive result until week 8 of the pregnancy.

The primary efficacy endpoint was ongoing pregnancy at week 10. Further clinical variables, as well as tolerability and side effects, were compared.

Baseline characteristics and stimulation outcome were similar between the 2 groups. The rate of ongoing pregnancy at week 10 did not significantly differ between the 2 arms of the study (29.2% with progesterone injection vs 31.2% with vaginal gel). Delivery and live birth rates were also similar (28.5% with progesterone injection vs 30.5% with vaginal gel).

Pregnancy outcome (gestational age at delivery, birthweight), the proportion of singleton vs multiple pregnancies, and status of the newborn were similar with the 2 regimens. Nonserious adverse events (breast disorders, gastrointestinal disorders, nervous system disorders) were reported by 45.4% of injection recipients vs 42.3% of vaginal gel recipients, and serious adverse events (ectopic pregnancy, ovarian hyperstimulation, miscarriage) were reported by 4.1% vs 5.8% of the patients, respectively. The differences were not significant.

Of the injection recipients, 57% experienced an injection-site reaction (pruritus, irritation, hematoma), whereas 50.8% of the vaginal gel users experienced vaginal discomfort (discharge, irritation, inflammation). The majority of the patients in both groups felt comfortable or very comfortable with the treatment, and over 75% of them were satisfied with the treatment.

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