Colorado Center for Reproductive Medicine, 799 E. Hampden Ave, Englewood, Colorado 80110, USA
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Abstract |
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Key words: assisted reproduction/Crinone/luteal support/progesterone/vaginal progesterone
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Introduction |
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In contrast with vaginal route findings, oral progesterone was inappropriate for inducing the endometrial transformations normally seen in the luteal phase (Bourgain et al., 1990) and providing adequate support during the luteal phase in IVF cycles (Licciardi et al., 1999
). The lack of proper endometrial effects seen with even large doses of oral progesterone has been linked to the high rate of progesterone metabolism during hepatic first-pass, which is responsible for a bioavailability of <10% (Nahoul et al., 1987
, 1993
). Hence, oral progesterone is not an acceptable option for luteal support in IVF.
Despite promising results, American clinicians have been notoriously reluctant to use vaginal progesterone in their IVF practice. This is due in part to concerns that vaginal progesterone might not provide sufficient plasma progesterone concentrations to ensure the high pregnancy rates (PR) reported by several groups in the USA (Centers for Disease Control, 1998; Gardner and Lane, 1998). The low concentrations of plasma progesterone reported by teams who used vaginal suppositories have fuelled these concerns (Schmidt et al., 1989
). The lack of a pharmaceutical product appropriately designed for vaginal use has also been a factor that has limited the use of vaginal administration. In fact, vaginal progesterone use has remained marginal in IVF programmes in the USA, despite promising results obtained with early vaginal formulations (Simon et al., 1986
; Sauer et al., 1987
; Schmidt et al., 1989
; Steingold et al., 1989
). The medical community also questioned the reliability of progesterone release and absorption from products that have not been thoroughly tested and/or not specifically formulated for vaginal use.
Now, with the availability of the controlled and sustained-release vaginal progesterone gel, Crinone® 8% (Serono Laboratories, Randolph, MA, USA) a pharmaceutical grade product exists for delivering progesterone vaginally. This product has been formally indicated for progesterone supplementation in assisted reproductive therapy (ART) by the Food and Drug Administration (FDA) and other European agencies including the British Medicine Control Agency (MCA). Approval by the FDA was based on the demonstration of product efficacy, even in complete absence of endogenous production of progesterone by the ovaries (Gibbons et al., 1998; Jobanputra et al., 1999
). In the present trial, the efficacy of single daily administration of the sustained-release progesterone vaginal gel, Crinone 8%, for luteal support was tested in a highly successful IVF programme having ongoing (>20 weeks) pregnancy rates that routinely exceed 50%.
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Materials and methods |
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Results from this group were compared with: (i) a group of control patients obtained by identifying 46 consecutive IVF patients who were enrolled beginning October 1997, had satisfied similar inclusion criteria, but had received luteal support from i.m. progesterone (50 mg/day); and (ii) historical IVF data reported for 1996 to the Society for Assisted Reproduction Therapy (SART) (CDC, 1998), i.e. the last set of data reported prior to Crinone use.
Study design
This was an open-label trial designed to assess efficacy and tolerability of the vaginal progesterone gel, Crinone 8%. A group of subjects (n = 43) was recruited to receive Crinone 8%, and the results were compared with those of two control groups. One comparison group consisted of a similar size sample of women (n = 46) undergoing IVF concurrently but receiving luteal support from progesterone supplied by i.m. injections (50 mg/day), while the second was based upon historical data from 1996 reported to SART (CDC, 1998).
Stimulation protocols
Study participants received ovarian stimulation according to a standardized protocol involving luteal phase gonadotrophin-releasing hormone (GnRH) agonist down-regulation. In accordance with this protocol, 0.5 mg of leuprolide acetate (Lupron®; TAP Pharmaceutical Inc., Deerfield, IL, USA), administered daily by s.c. injection, was initiated during the luteal phase. This dose was continued until ovarian suppression was achieved, as confirmed by oestradiol concentrations and sonography. This dose was reduced by one-half with the onset of ovarian stimulation and continued until human chorionic gonadotrophin (HCG) administration. Ovarian stimulation was initiated using human menopausal gonadotrophin (HMG) or recombinant FSH. The typical starting dose was set at 225 to 450 IU/day for 5 days, based on prior responses to HMG and/or basal FSH values. Further dosing adjustments were based on ultrasound findings and plasma hormone concentrations, as previously described (Schoolcraft et al., 1991; Meldrum, 1992
, 1996
). Briefly, when at least two follicles were
18 mm in diameter, 10 000 IU of HCG (Profasi®; Serono Laboratories, Inc., Randolph, MA, USA) were administered. Oocyte retrieval was performed 35 to 36 h after HCG administration.
Less than 10% of the patients designated as poor responders were administered a different ovulation stimulation treatment known as `microflare' (Schoolcraft et al., 1997). This treatment consisted of 0.02 mg leuprolide acetate, administered twice daily by s.c. injection beginning on cycle day 3, following 24 weeks of oral contraceptive use. On cycle day 5, HMG or recombinant FSH treatment was initiated at the dose of 600 IU/day, while continuing leuprolide acetate. The remainder of the microflare protocol was similar to that of the standardized protocol, which is routinely used in our practice. The frequency in which the microflare protocol was employed was similar (<10%) in both control groups.
Luteal support
Luteal support was initiated 2 days after oocyte retrieval irrespective of whether this was provided from the vaginal gel or i.m. injections. In the vaginal progesterone gel study group, 43 women undergoing IVF cycles applied single daily doses of Crinone 8%. In either case, luteal support was continued until the pregnancy test was performed and for up to 12 weeks in case of pregnancy. The 46 other infertile women undergoing concurrent IVF cycles who served as a control group received luteal support from daily i.m. injections of progesterone (50 mg).
Determination of pregnancy status
Pregnancy status was determined by serum ß-HCG concentration approximately 2 weeks after embryo transfer (total PR), by ultrasounds 24 weeks later (clinical PR), and by counting live births. Biochemical pregnancy wastage was defined as any ß-HCG value >5 mIU/ml that did not evolve into a clinical pregnancy [i.e. biochemical (total PR) clinical PR]. Total pregnancy wastage was defined as the number of positive pregnancies (total PR), which did not evolve into a live birth [i.e. biochemical (total) PR live births]. All PR data were assessed by reference to the number of embryo transfers, as by design the study compared two forms of luteal support which possibly affected embryo implantation.
Patient acceptability
The acceptability of vaginal progesterone gel was assessed using a patient questionnaire that was completed by each subject after their last administration of Crinone 8%. Subjects were asked to rank their overall experience with the use of Crinone 8% on degree of difficulty of administration, messiness, presence of pain and interference with intercourse. A scale of 1 (very much) to 7 (not at all) was used to assess the subject's overall experience with the use of Crinone 8% in regard to these factors. In addition, subjects who had previously used other formulations were asked to rank their experience with the use of Crinone 8% versus the use of progesterone given by injection or suppository: easier to use, less painful, takes less time to administer and preferred method. A scale of 1 (strongly agree) to 7 (strongly disagree) was used to assess how each subject's overall experience with Crinone 8% compared with other previously used progesterone formulations on these aspects of treatment.
Statistical analysis
Although the study was not designed to determine equivalence between i.m. progesterone and Crinone 8%, statistical testing was done as a descriptive analysis. Comparable results in the Crinone 8% and both control groups would be considered supportive for demonstrating efficacy of Crinone 8%.
The three groups of IVF patients were compared using Student's t-test or Fisher's exact test, with two-tailed comparisons, or Wilcoxon rank sum test, with one-tailed comparisons. 2 statistics were used to analyse discontinuous data.
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Results |
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Overall, acceptability of Crinone 8% when used daily for luteal support in IVF was excellent (see Table III). Of the 43 women who responded to the questionnaire, 55.8% had no difficulty administering the gel. For 46.5% of the women, the gel did not at all interfere with intercourse.
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Women who responded to this questionnaire and had previously used progesterone suppositories agreed that the gel was easier to use (13/18; 72.2%), less painful (9/18; 50%) and less time-consuming (11/18; 61.1%). Furthermore, a majority (15/18; 83.3%) of these women agreed that they preferred treatment with the vaginal gel compared with suppositories.
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Discussion |
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In IVF cycles, it is difficult to sort out the respective roles of exogenous and endogenous progesterone on uterine receptivity and pregnancy maintenance. Because of the large number of functional corpora lutea normally present in IVF cycles, the endogenous production and circulating concentrations of progesterone commonly exceed menstrual cycle findings. Yet, despite the higher progesterone production, a meta-analysis confirmed that luteal support improves the outcome of IVF cycles in which a GnRH-agonist is used (Soliman et al., 1994). In this meta-analysis, improvements in pregnancy rates were found when luteal support was provided either with repeated HCG administrations or exogenous progesterone. Hence, because of the inherent difficulty in assessing the specific role of exogenous progesterone in the presence of large endogenous production, the efficacy of the new controlled and sustained-release vaginal gel (Crinone 8%) was tested in women totally deprived of endogenous progesterone. Achieving endometrial receptivity in women with premature ovarian failure was considered the best evidence of efficacy of luteal support provided by this controlled and sustained-release formulation. In donor egg IVF recipients, twice-daily (Gibbons et al., 1998
) and once-daily administration of 8% progesterone gel (Jobanputra et al., 1999
) reliably resulted in in-phase endometrial biopsies and pregnancy rates similar to those seen when luteal support was provided by i.m. injections. The fact that the vaginal gel succeeded at priming uterine receptivity and maintaining pregnancy even in the complete absence of endogenous progesterone provided the best possible evidence of product efficacy.
It remained important, however, to survey the outcome of regular IVF cycles as well as patient acceptability when luteal support is provided with the vaginal gel. All of the 43 women in whom luteal support was initiated with the vaginal gel remained on their initially prescribed regimen for their entire infertility treatment cycle. The majority of the 13 subjects who had prior experience with i.m. progesterone (69%) preferred Crinone 8% to i.m. injections for several reasons.
The strength of the present trial evaluating luteal support from the vaginal progesterone gel resides in the high pregnancy rates regularly achieved by the IVF programme that conducted this testing. In conditions featuring historically high pregnancy rates, a possibly inadequate efficacy of luteal support from the new vaginal gel presumably would have become more promptly apparent.
Results obtained with the vaginal progesterone gel were compared to those seen in a comparably sized group of 46 women who underwent IVF during the same period. While women were not randomly assigned to either i.m. or vaginal progesterone, the control group was nonetheless arbitrarily composed. It consisted of 46 IVF patients not included in the vaginal progesterone study mainly due to geographical reasons, which precluded the multiple evaluations required by the study protocol, but who satisfied all the other inclusion criteria.
The dosing regimen chosen for administering the vaginal progesterone gel was one application of the Crinone 8% per day until a pregnancy test was performed. This treatment regimen was continued for a total of up to 12 weeks in case of pregnancy. Selection of the once-daily regimen was based on evidence in the donor egg IVF model showing that histological findings and pregnancy rates for the twice-daily and once-daily regimens of Crinone 8% were equivalent (Jobanputra et al., 1999).
The convenience of single daily administration of Crinone should be obvious. In addition, the fact that relatively small amounts of progesterone (90 mg/day) can provide efficient luteal support is a consequence of direct vagina-to-uterus transport that characterizes vaginal administration of progesterone (Miles et al., 1994; de Ziegler, 1995
; Bulletti et al., 1997
; Fanchin et al., 1997
). The controlled and sustained-release gel optimizes this property inherent to the vaginal route of administration since delivery is provided over time (Bulletti et al., 1997
). One important practical consequence of the direct vagina-to-uterus transport of vaginally administered progesterone or `first uterine pass effect' is the uselessness of plasma progesterone measurements. Because of the direct transport to the uterus, proper uterine impregnation of progesterone is achieved, despite low peripheral concentrations (Cicinelli et al., 2000
).
Our results show that luteal support in IVF, including during early pregnancy, can be effectively provided by once-daily administration of the controlled and sustained-release progesterone gel, Crinone 8%. Minimal side effects make this approach more acceptable to a greater number of patients than daily i.m. injections that are both painful and associated with other complications such as sterile abscesses. The fact that, historically, pregnancy rates in excess of 50% were commonly achieved in this programme and remained unchanged when luteal support was provided from vaginal progesterone supports evidence of efficacy for this product. The origins of our high pregnancy rate are multi-factorial and revolve around a meticulous attention to detail. Notably, we believe that most important of these factors are the quality of the culture media used (Gardner and Schoolcraft, 1999), the technique of non-traumatic embryo transfer under ultrasound guidance (Schoolcraft et al., 1999
), and the use of selected stimulation protocols for poor responders (Schoolcraft et al., 1997
).
In conclusion, our data showed that progesterone delivered from the new controlled and sustained-release vaginal gel appears to be as effective as daily i.m. progesterone at providing luteal support, thus rendering painful injections or multiple daily dosing with other vaginal progesterone formulations unnecessary.
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Acknowledgments |
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Notes |
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References |
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Submitted on October 27, 1999; accepted on March 15, 2000.