Subcutaneous and Vaginal Progesterone for LPS Found to be Equally Effective in Improving IVF Pregnancy Outcomes

Progesterone used for luteal phase support (LPS) is available commercially in different formulations, including oral capsules, intramuscular injection in oil, capsules for vaginal or rectal administration, and vaginal gel. Recently, water-soluble and subcutaneously injectable progesterone have been developed. To compare the efficacy and tolerability of the newly developed subcutaneous progesterone preparation with vaginal P gel for LPS, a first prospective, randomized, large, noninferiority, placebo-controlled study reported similar effectiveness and tolerability of both the preparations with respect to ART outcomes. The findings of the study have been published in the journal, Fertility and Sterility.

Gillian Lockwood, Medical Director, Midland Fertility Services, United Kingdom, and co-workers, compared the efficacy, safety, and tolerability of subcutaneous progesterone (Prolutex;IBSA Institut Biochimique SA) with the vaginal progesterone gel (Crinone; Merck Serono) for LPS in IVF/ICSI treatment cycles. The patients, included in this study, were from 13 different European fertility clinics, and all the ART procedures were done as per the site-specific protocols.

In this study, 683 patients included in the intention-to-treat (ITT) population, were randomized to two treatment groups; one subset was injected with Prolutex subcutaneously at a dose of 25 mg/day (n=339), and the other with Crinone 8%, applied intravaginally, at 90 mg/day (n=344). The patients were given the progesterone formulations on the day of oocyte retrieval and treated with adequate doses for up to 10 weeks. Among the ITT patients, 640 pursued the treatment as per the protocol and hence were included in the per protocol (PP) population.

It was found that the ongoing pregnancy rates at 10 weeks of treatment for the Prolutex and Crinone groups were 27.4% and 30.5%, respectively. The difference between the two treatment groups (-3.09%) was non-significant (95% CI9.91 to 3.73). In addition, among the PP population, no significant differences in ongoing pregnancy rates were observed between both the groups. Similar results were noted with respect to the secondary variables like implantation rate, positive b-hCG test rate, pregnancy rate, early spontaneous abortion rate, delivery rate, live birth rate, and newborn status (Table 01).

Table 01: Primary and secondary endpoints of two treatment groups

Outcomes ITT population PP population
Prolutex Crinone P value
(95% CI)
Prolutex Crinone P value
(95% CI)
Primary outcome
Ongoing pregnancy n (%)
93
(27.4)
105
(30.5)
.40
(-9.91 to 3.73)
93
(29.2)
100
(31.2)
.61
(-9.12 to 5.13)
Secondary outcomes
Implantation rate n (%)
22.6
(35.0)
23.1
(33.1)
.85
(-5.75 to 4.72)
22.8
(35.1)
22.7
(32.9)
.97
(-5.16 to 5.39)
Positive beta-hCG test n (%) 134
(39.5)
148
(43.0)
.35
(-10.89 to 3.90)
134
(42.0)
141
(43.9)
.62
(-9.60 to 5.77)
Clinical pregnancy n (%) 103
(30.4)
113
(32.9)
.49
(-9.45 to 4.52)
103
(32.3)
108
(33.6)
.72
(-8.65 to 5.94)
Early spontaneous abortion n (%) 14
(4.1)
14
(4.1)
.97
(-2.92 to 3.04)
14
(4.4)
14
(4.4)
.99
(-3.15 to 3.20)
Delivery and live births n (%) 91
(26.8)
103
(29.9)
.37
(-9.87 to 3.68)
91
(28.5)
98
(30.5)
.58
(-9.08 to 5.08)


On the whole, the findings showed comparable occurrence of treatment-related serious and nonserious adverse events in Prolutex and Crinone groups. Additionally, the treatment was found to be comfortable and satisfying for the patients in the two groups.

Although the need for LPS is well-recognized, there is a lack of consensus on the most favorable drug, timing of initiation, duration of use, and the route of administration. According to a report of the American Society for Reproductive Medicine (ASRM) and Society for Reproductive Endocrinology and Infertility (SREI) (Fertility and Sterility, 2008), progesterone supplementation is recommended in IVF cycles owing to its association with increased pregnancy rates in comparison to placebo or no treatment.

In a recent web-based survey on the global real-life LPS practices in assisted reproduction, Vaisbuch et al (Reproductive Biomedicine Online, 2014) observed that > 90% of the practitioners use vaginal progesterone, either as a single entity or in combination with intramuscular progesterone. The survey investigated the different routes, timing, dosage of progesterone for LPS in data collected from 82 countries involving 284,600 treated IVF cycles per year. The researchers highlighted a shift in the direction of evidence-based and unified approach in the use of LPS during ART cycles when compared to their earlier survey in 2009. Similarly, an earlier Cochrane review (Cochrane Database of Systematic Reviews, 2011) assessed the different drugs, duration, and routes of administration for LPS and concluded that there is lack of significant evidence supporting any particular route or duration of progesterone administration in improving clinical pregnancy rates.

References

  • Lockwood G, Griesinger G, Cometti B, et al. Subcutaneous progesterone versus vaginal progesterone gel for luteal phase support in in vitro fertilization: a noninferiority randomized controlled study. Fertil Steril. 2014 Jan;101(1):112-119.e3.
  • Practice Committee of American Society for Reproductive Medicine in collaboration with Society for Reproductive Endocrinology and Infertility: Progesterone supplementation during the luteal phase and in early pregnancy in the treatment of infertility: an educational bulletin. Fertil Steril. 2008:90:S150-S153.
  • Vaisbuch E, de Ziegler D, Leong M, Weissman A, Shoham Z. Luteal-phase support in assisted reproduction treatment: real-life practices reported worldwide by an updated website-based survey. Reprod Biomed Online. 2014 Mar;28(3):330-5.
  • van der Linden M1, Buckingham K, Farquhar C, Kremer JA, Metwally M. Luteal phase support for assisted reproduction cycles. Cochrane Database Syst Rev. 2011 Oct 5;(10):CD009154.

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