Progesterone supplementation during cryopreserved embryo transfer cycles: efficacy and convenience of two vaginal formulations. Artificial versus stimulated cycles for endometrial preparation prior to frozen-thawed embryo transfer. Glucocorticoid administration during transfer of frozen-thawed embryos: a prospective, randomized study. Delaying the initiation of progesterone supplementation until the day of fertilization does not compromise cycle outcome in patients receiving donated oocytes: a randomized study. A prospective randomized study comparing intramuscular with intravaginal natural progesterone in programmed thaw cycles. Experience with a novel vaginal progesterone preparation in a donor oocyte program. Endometrial preparation for frozen-thawed embryo transfer with or without pretreatment with gonadotropin-releasing hormone agonist. Pituitary suppression in ultrasound-monitored frozen embryo replacement cycles. A randomised study. Low-dose aspirin for oocyte donation recipients with a thin endometrium: prospective, randomized study. Low-dose human chorionic gonadotropin during the proliferative phase may adversely affect endometrial receptivity in oocyte recipients. The use of gonadotrophin-releasing hormone analogues in women receiving oocyte donation does not affect implantation rates. Luteinizing hormone affects uterine receptivity independently of ovarian function. The use of long- and short-acting forms of gonadotrophin-releasing hormone analogues in women undergoing oocyte donation. Prospective randomized trial to evaluate the efficacy of a vaginal ring releasing progesterone for IVF and oocyte donation. Low-dose glucocorticoids after in vitro fertilization and embryo transfer have no significant effect on pregnancy rate.
Sequential exogenous oestradiol and progesterone are often used to prepare the endometrium in frozen embryo transfer (FET) cycles. This open-label, randomized study compared the efficacy and acceptability of self-administered once daily vaginal progesterone gel and vaginal micronized progesterone tablets (three times daily) for luteal support in FET cycles. An Asian population of women (aged < or = 45 years) were assigned randomly to receive progesterone gel (90 mg, once daily, n= 100) or vaginal micronized progesterone tablets (200 mg, three times daily, n= 100). All received oestradiol from day 2 of the menstrual cycle, for at least 10 days (or until endometrial thickness was > or =8 mm), before self-administering progesterone for 2 days before FET and up to 14 weeks afterwards if pregnancy occurred. Clinical pregnancy rates (31% for gel and 28% for tablets) and implantation rates (9.8% and 8.8%, respectively) were not significantly different between the treatment groups. Asian women using once daily progesterone gel found the gel easy to use and comfortable, and preferred it to their previous experience of vaginally administered tablets. In summary, once-daily vaginal progesterone gel has similar efficacy to vaginal tablets and is associated with high patient satisfaction. The objective of this study was to compare the implantation rate, pregnancy rate and endometrial thickness of frozen-thawed embryo transfers using endometrial preparation with either an artificial cycle or stimulated cycle. This was a prospective randomized trial at a single academic IVF centre. Seventy-seven patients undergoing artificial cycles received oral oestradiol; patients with endometrium < 7 mm on day 9-10 were switched to vaginal oestradiol. Eighty-six patients undergoing stimulated cycles received recombinant FSH followed by human gonadotrophin hormone injection. Vaginal progesterone was begun 2 or 3 days prior to embryo transfer. There was no difference in implantation rate (8.5% versus 7.3%), pregnancy rate (16% versus 13%), cancellation rate (both 23%) or endometrium thickness (8.7 +/- 1.1 mm versus 8.7 +/- 1.0 mm) between artificial and stimulated cycles. Stimulated cycles had a higher incidence of thin endometrium (27% versus 5%, P < 0.01). In artificial cycles, patients switched to vaginal oestradiol had improved pregnancy rate (31%) versus patients who received oral oestradiol alone (13%) (P = 0.05). It is concluded that artificial and stimulated cycles produce comparable pregnancy rates, implantation rates, cancellation rates and endometrial thickness, although stimulated cycles have a higher incidence of thin endometrium. Vaginal oestradiol supplementation improved implantation rates. To establish whether there is any improvement in pregnancy and implantation rates after administration of "low-dose," long-acting glucocorticoids during transfer of cryopreserved-thawed embryos.
                An IVF unit in a university hospital.
                Prospective, randomized study. Ninety-nine consecutive transfer cycles of frozen-thawed embryos to the uterine cavity of randomly chosen women diagnosed as having tubal factor infertility only. Fifty-two patients underwent transfer of frozen-thawed embryos and received 0.5 mg of dexamethasone; 47 women (control group) did not receive the drug during transfer.
                Normal ovulatory patients with tubal factor infertility.
                Oral dexamethasone administration before, during and after transfer of thawed embryos.
                Pregnancy and implantation rates.
                The pregnancy rate was 13.5% (7/52) in patients treated with the "low-dose" regimen of dexamethasone compared with 12.8% (6/47) in the control group. The implantation rate was similar.
                Our results demonstrated that the use of 0.5 mg dexamethasone for an immuno-suppressive effect, administered for a short period to patients diagnosed as having "pure" tubal factor infertility, did not improve the implantation or pregnancy rates. To determine whether the initiation of P supplementation as artificial luteal phase support (day -1, day 0, or day +1 of egg donation) in extensive programs of ovum donation influences cycle cancellation, pregnancy outcome, and implantation rate in day 3 embryo transfers.
                Prospective randomized trial.
                Oocyte donation program at the Instituto Valenciano de Infertilidad, Valencia, Spain.
                Three hundred recipients with normal ovarian function, absence of uterine anomalies, and undergoing their first egg donation were recruited between September 2003 and September 2004.
                A computer-based randomization divided the recipients into three groups when hCG was administered to their matched donors. The first group (group A) started P supplementation the day before oocyte retrieval; the second group (group B) started P supplementation on the day of the oocyte retrieval; and the third group (group C) started P supplementation 1 day after the egg retrieval once fertilization was confirmed.
                Implantation, pregnancy, and ongoing pregnancy rates were the primary outcome measures considered. The secondary outcome measure was the cancellation rate, especially due to fertilization failure.
                Global cancellation rate and cancellation rate due to fertilization failure were significantly higher in group A (12.4% and 8.2%, respectively) than in group C (3.3% and 0%, respectively). Reproductive outcome was similar in all the groups except for a higher biochemical pregnancy rate in group A (12.9%) than in groups B (6.6%) and C (2.3%).
                Initiation of P on day +1 of embryo development decreases cancellation rates of day 3 embryo transfers in extensive programs of ovum donation without any deleterious effect on pregnancy outcome or implantation rate. A simple programmed thaw cycle is described, during which the endometrium is prepared with oral oestradiol, followed by a natural progesterone source. This method involves minimal blood tests and uses inexpensive medications. Originally, an i.m. progesterone-in-oil preparation was used. Although highly successful in achieving high serum progesterone concentrations, the daily injections of the oily compound were found to be problematic from the patients' perspective. To examine the possibility of replacing the injectable progesterone with a vaginal preparation we conducted a prospective randomized study of 1 year's duration, during which time 170 and 184 thawing cycles were done with injectable and vaginal progesterone respectively. Although the progesterone blood concentrations obtained with the injectable preparation were more than twice those obtained with the vaginal progesterone, the clinical pregnancy rates (defined as percentage thawing cycles with gestational sac(s)/embryo transfer as demonstrated on ultrasound, 4 weeks after embryo transfer) were similar for both groups (15.9 and 16.8% respectively). Implantation and abortion rates were also comparable. These results agree with previous reports of higher uterine progesterone concentrations after the vaginal application. We conclude that the combination of oral oestradiol and vaginal progesterone is an effective, simple and inexpensive approach for programmed thaw cycles. To compare the efficacy of a vaginal progesterone preparation with our standard IM preparation within a donor egg program.
                Prospective randomized trial.
                Donor egg program at a university assisted reproductive therapy program (Jones Institute for Women's Health).
                Couples accepted into the donor egg program because of either premature ovarian failure or evidence of diminished ovarian reserve.
                Women were randomized into either a group receiving IM progesterone replacement or a group receiving vaginal progesterone replacement. Both groups underwent Estraderm patch/progesterone treatment in a mock cycle leading to an endometrial biopsy on day 26 followed by a second cycle in which ET was performed. Subjects with residual ovarian function received a GnRH agonist. In the IM treatment group, 100 mg was administered from cycle days 15 to 27. In the vaginal treatment group, Crinone 8%, a polycarbophil-based gel preparation containing 90 mg of micronized progesterone, was administered twice daily from the evening of day 14.
                Endometrial histology, serum levels of progesterone (on days 13, 17, 20, 24, and 26), the occurrence of pregnancy, implantation rate, and pregnancy outcome.
                Fifty-four women randomized into the vaginal progesterone treatment group and 18 women in the IM treatment group achieved ET. Mean serum progesterone levels were higher in the IM treatment group than in the Crinone group. Endometrial histology was "in phase" for all subjects in both groups. Clinical pregnancies were observed in 26 of 54 women and 5 of 18 women in the Crinone and IM progesterone groups, respectively. The ongoing pregnancy rate (PR) of 31% (17/54) and implantation rate of 23% in the subjects receiving Crinone was not statistically different from the IM progesterone group's ongoing PR of 22% (4/18) and implantation rate of 18%.
                Vaginal progesterone replacement with the polycarbophil gel preparation was as effective as IM progesterone in producing clinical and ongoing pregnancies within our donor egg program in the dosages administered. To test the efficacy of endometrial preparation with exogenous steroids, without pretreatment with gonadotropin-releasing hormone (GnRH) agonist, in women with normal ovarian function.
                Prospective randomized study.
                Private outpatient infertility clinic.
                Two hundred ninety-six women undergoing frozen-thawed embryo transfer.
                In group 1 (146 patients), depot GnRH agonist was administered in the luteal phase; treatment with 17beta-estradiol transdermal patches at steadily increasing dosage from 100 to 300 microg was then given for at least 12 days. In group 2 (150 patients), endometrial preparation began on day 1 of menstrual cycle. The starting dose was 200 microg; this was increased to 300 microg after 7 days.
                Pregnancy, abortion, implantation and cancellation rates.
                In group 2, six cycles (4%) were cancelled due to evidence of ovulation. Groups were similar in the percentage of embryos that survived freezing-thawing (77.1% in group 1 and 76.6% in group 2) and in the number of embryos transferred per patient (2.1 +/- 0.6 and 2.1 +/- 0.7, respectively). Groups 1 and 2 did not differ significantly in rates of pregnancy (19.7% and 24.1%), abortion (17.8% and 11.7%), and implantation (10.4% and 11.9%).
                Endometrial preparation for frozen-thawed embryo transfer based exclusively on steroid administration appears to be as effective as the more conventional protocol involving preliminary desensitization with a GnRH agonist. This simplified protocol reduces costs, minimizes pharmacologic treatment, and increases patient compliance. This study was designed to assess the value of using a gonadotrophin-releasing hormone (GnRH) agonist prior to exogenous steroid supplementation for endometrial preparation in frozen-thawed embryo replacement (FER) cycles.
                A prospective randomized trial of 234 patients undergoing FER cycles was conducted. The study population was randomly divided into two groups according to a computer-generated list. In group A (n = 117), a daily dose of 6 mg of oral estradiol valerate was initiated on menstrual day 1 following pituitary suppression using 400 mcg buserelin acetate daily. In group B (n = 117), the same dose of estradiol valerate was initiated on day 1 of bleeding without prior GnRH agonist therapy. In both groups, ovulation monitoring was not undertaken and progesterone pessaries (800 mg daily) were administrated when the endometrial thickness had reached 8 mm or more with embryo transfer taking place 2 days later.
                The two groups were comparable with respect to cause of infertility, age at stimulation (32.8 +/- 4 vs 33.2 +/- 3.9 years, P = 0.4), basal FSH level (6.3 +/- 1.7 vs 6.4 +/- 2 IU/l, P = 0.5), number of oocytes collected (16.9 +/- 7.3 vs 16.5 +/- 7.4, P = 0.7) and fertilized normally in the retrieval cycle (11.5 +/- 4.9 vs 11 +/- 4.9, P = 0.4) and number of embryos cryopreserved (6.6 +/- 3.6 vs 6.2 +/- 3.6, P = 0.3). There was no significant difference between the two groups in age at frozen replacement (33.6 +/- 4.2 vs 34 +/- 3.9 years, P = 0.4), duration of the proliferative phase (20.7 +/- 8.6 vs 21 +/- 9.2 days, P = 0.7) and number of thawed embryos replaced (2.3 +/- 0.6 vs 2.2 +/- 0.6, P = 0.2). However, compared with group B, group A achieved significantly higher pregnancy (37.6% vs 24%, OR 1.8, 95%CI 1.1-3.4), clinical pregnancy (24% vs 11.3%, OR 2.5, 95%CI 1.2-5.5) and live birth rates (20% vs 8.5%, OR 2.9, 95%CI 1.2-8).
                Medicated frozen embryo replacement cycles timed by endometrial thickness measurement alone without monitoring or suppression of ovarian activity are associated with reduced outcome. To evaluate the effect of low-dose aspirin use in oocyte donation recipients with an endometrial thickness of < 8 mm.
                A prospective, randomized study.
                An oocyte donation program in a private infertility practice.
                Twenty-eight recipients undergoing oocyte donation who failed to develop an endometrial thickness of at least 8 mm in a previous evaluation cycle.
                Fifteen recipients received low-dose aspirin (81 mg/d) in addition to standard hormone replacement for an oocyte donation cycle. The remaining 13 recipients did not receive aspirin.
                Clinical pregnancy rates, delivery rates, implantation rates, and change in endometrial thickness were compared in the aspirin and nonaspirin groups.
                There was no demonstrable increase in endometrial thickness in the aspirin-treated group. However, there was a statistically significant increase in implantation rates in the aspirin-treated group (24% versus 9%) and in implantation rates and clinical pregnancy rates in the aspirin-treated group when the final endometrial thickness was < 8 mm.
                Low-dose aspirin therapy improves implantation rates in oocyte donation recipients with a thin endometrium. The effect of low-dose human chorionic gonadotropin (hCG) administration in the proliferative phase of oocyte recipients was investigated in a prospective randomized trial. Sibling oocytes from the same donor were shared at random among two different recipients. In group I oocyte recipients received 750 IU of hCG every three days concomitant to endometrial preparation with estradiol until hCG injection to the donor, whereas in group II recipients received no hCG during endometrial priming with estradiol. Endometrial thickness was significantly lower in group I compared with group II, although similar endometrial thickness was detected during the mock cycle. Pregnancy rates were significantly lower in group I than in group II (13.6% vs. 45.4%, p<0.05). Implantation rates were also significantly lower in group I (1.7% vs. 22.4%, p<0.01). The study was discontinued prematurely for ethical reasons when 22 cycles were completed, as pregnancy rates were very low in group I. In conclusion, hCG administration in the proliferative phase might directly affect endometrial proliferation and receptivity. There is conflicting clinical evidence suggesting a positive role for gonadotrophin-releasing hormone analogues (GnRHa) on implantation in humans. This potential effect was evaluated in this study taking the oocyte donation programme as a model. Patients were randomly allocated into one of the two treatment groups: group I received simultaneous treatment with GnRHa and steroids, and group II only received exogenous steroid replacement. An analysis of the donors and semen quality showed similarity between recipient groups. There was no significant difference between groups in the number and quality of embryos replaced, clinical pregnancy and implantation rates. In summary, using a model in which the endometrium can be analysed independently of the embryos, the results suggest that GnRHa are neither effective nor detrimental for embryo implantation in humans. Previous studies have suggested that LH, in addition to its well-known effects on the ovary, may exert direct effects on the uterus. This study evaluated the effects of mid-cycle administration of human chorionic gonadotrophin (HCG), which signals through the LH receptor, on endometrial thickness and uterine receptivity in two groups of women lacking ovarian activity and receiving embryos from an oocyte donation programme. Patients in one group still had ovulatory cycles, but their ovarian function was suppressed by pituitary down-regulation with a gonadotrophin-releasing hormone (GnRH) agonist in the embryo transfer cycle, resulting in low endogenous LH concentrations. Patients in the other group were menopausal women whose pituitary function was not down-regulated in the embryo transfer cycle and whose endogenous LH concentrations were thus high. Patients in each of the two groups were randomized into two subgroups. Patients in one subgroup were given 5000 IU of HCG 2 days before oocyte recovery in the corresponding donor. Patients in the other subgroup received placebo at the same time. Oocytes from each donor were randomly distributed between one patient from the HCG subgroup and one patient from the placebo subgroup in each patient group. Endometrial growth and secretory transformation were stimulated by sequential treatment with oestradiol valerate and progesterone. In women with low endogenous LH receiving placebo, endometrial thickness stopped increasing at the beginning of secretory transformation. Mid-cycle HCG administration resulted in a continuous increase in endometrial thickness through this period, improved the implantation rate after embryo transfer in these women (30.6 versus 20.7%) and augmented the number of multiple pregnancies. No similar stagnation of endometrial thickness and no effects of mid-cycle HCG administration on endometrial thickness, the implantation rate and the number of multiple pregnancies were found in women with high endogenous LH. It is concluded that endometrial maturation is disturbed in women with low endogenous LH but can be rescued by mid-cycle stimulation of LH receptor with exogenous HCG in the absence of ovarian activity. Evidence accumulated in in-vitro fertilization (IVF) cycles suggests that the use of long-acting forms of gonadotrophin-releasing hormone analogues (GnRHa) for pituitary desensitization may impair the outcome of IVF as compared to classical short-acting formulations. Whether the negative effects are directed against the corpus luteum, the endometrium, or both is unknown. However, the presence of high affinity binding sites for gonadotrophin-releasing hormone (GnRH) in the human endometrium suggests a possible role of these analogues on this target organ, affecting embryo implantation. In the present study, we tested direct effects of two different forms of GnRHa on implantation using the ovum donation model. Patients were prospectively allocated to one of the three study groups: the short-acting form of the analogue leuprolide acetate (group I; n=64), the long-acting form of the same analogue (group II; n=58), and the long-acting preparation of the analogue tryptorelin (group III; n=61). A total of 68 cycles of embryo transfer was carried out in group I, whereas 67 were performed in group II and 65 in group III. Cancellation rates were respectively 18.1, 17.3 and 18.8% because of bleeding while being on the waiting list for anonymous oocyte donation. The number of oocytes donated, fertilization rates and embryos replaced in each group were similar. As a result, pregnancy rate per transfer was 38.2, 49.3 and 44.6% respectively. Implantation rates per embryo replaced were respectively 13.4, 19.1 and 17.0%. These data suggest that the use of a long-acting form of GnRHa provides success rates similar to the short-acting preparations, resulting in more convenient medication for patients with ovarian function included in ovum donation programmes. A polysyloxane vaginal ring containing 1g of natural progesterone was developed as luteal supplementation for women treated with IVF-embryo transfer and for agonadal women participating in an oocyte donation programme. The ring provides continuous release of progesterone (10-20 nmol/l) for 90 days. The efficacy of this form of progesterone supplementation was evaluated in two multicentre prospective randomized trials. IVF-embryo transfer trial: After oocyte aspiration, 505 women were randomly allocated to progesterone supplementation with vaginal ring or i.m. progesterone (50 mg/day). The clinical pregnancy rate was 36.6% in both groups. Implantation rate was 15.9% in the vaginal ring and 16.0% in i.m. progesterone. Oocyte donation trial: After endometrial proliferation with micronized oestradiol, 153 women were allocated to progesterone replacement with a vaginal ring or i.m. progesterone (100 mg/day). Clinical pregnancy rate was 39.8 and 28.6% respectively. Implantation rate was significantly higher with the vaginal ring compared with i.m. progesterone (19.9 and 11.6% respectively, P = 0.006). The vaginal ring is a novel development which provides continuous release of progesterone for 90 days. In IVF-embryo transfer, its effectiveness is similar to daily i.m. injections. In oocyte donation the ring provides a progestative milieu which improves the implantation rate and eliminates the discomfort of daily i.m. injections. To determine the effect on pregnancy rate (PR) of low-dose glucocorticoid treatment in cycles without micromanipulation.
                Randomized, prospective, double-blinded, placebo-controlled trial.
                One university-based tertiary infertility center and two private infertility centers.
                All patients receiving standard stimulation IVF-ET or transfer of cryopreserved embryos at the participating facilities from January to September 1993 were asked to participate in this study. Patients having micromanipulation were excluded from this study.
                Participating patients were randomized to either 16 mg oral 6-alpha-methylprednisolone for four evenings starting the evening of retrieval or the evening before thawing cryopreserved embryos or to placebo administered in an identical fashion. Both groups were treated with 250 mg oral tetracycline four times per day starting with initiation of the study medication and continuing for 4 days. Cryopreservation and stimulation cycles were managed according to pre-established protocols for all patients. A clinical pregnancy was confirmed by an appropriately rising hCG titer and a gestational sac on ultrasound.
                A total of 206 stimulation patients and 61 cryopreservation patients were randomized and had an ET. Patient characteristics were similar between groups. The clinical pregnancy and implantation rates between placebo and glucocorticoid groups were 35.9% versus 40.8% and 12.8% versus 11.7% for stimulation cycles and 30.3% versus 25% and 9.9% versus 7.4% for cryopreservation cycles, respectively. None of these differences were statistically significant.
                Glucocorticoid plus antibiotic treatment at these doses for transfers of nonmicromanipulated embryos does not appear to have a significant effect on pregnancy or implantation rates.
There is insufficient evidence to recommend any one particular protocol for endometrial preparation over another with regard to pregnancy rates after embryo transfers. These were either frozen embryos or embryos derived from donor oocytes. However, there is evidence of a lower pregnancy rate and a higher cycle cancellation rate when the progesterone supplementation is commenced prior to oocyte retrieval in oocyte donation cycles. Adequately powered studies are needed to evaluate each treatment more accurately.