High Doses Of Gonadotropins Research Articles

Monozygotic twins in infertile patients with advanced maternal age: case reports and review of the literature

To report two cases of successful monozygotic twin pregnancies in women undergoing infertility treatment and to review possible etiologic factors. Case report and review of the literature. University of Toronto-affiliated infertility clinic. A 43-year-old woman and a 44-year-old woman with history of secondary infertility. In vitro fertilization and ET. Monozygotic twin pregnancy. Delivery of two sets of monozygotic twins. The only identified potential risk factors for monozygotic twins are maternal age and assisted reproductive technologies. Both patients reported here were aged >40 years and underwent assisted reproduction procedures, including high-dose gonadotropin stimulation, embryo culture, and, in case 2, intracytoplasmic sperm injection plus assisted hatching.

Fewer medications for in vitro fertilization can be better: thinking outside the box

Minimal stimulation or mild stimulation protocols for in vitro fertilization offer many advantages for all patients, but especially for low and high responders. In the current practice of reducing the number of embryos transferred to a maximum of two for a significant number of patients, using aggressive and high-dose gonadotropins to obtain a large, and sometimes excessive, number of oocytes should be questioned.

Combined Jugular and Subclavian Vein Thrombosis Following Assisted Reproductive Technology: The Mystery Is out

In assisted reproductive technology (ART) high doses of human menopausal gonadotropins are used to induce controlled ovulation. This technology puts women at high risk of developing the ovarian hyperstimulation syndrome and thombotic events.Objective: To discern the reason for predilection of combined jugular and subclavian following ART.Methods: Women who developed combined jugular and subclavian vein thrombosis following assisted reproductive technology were included in the study. The thrombotic events were demonstrated by ultrasound Doppler or computerized tomography angiography. All women were interviewed and data obtained from outpatient clinic and hospital medical charts. Magnetic resonance imaging and complete thrombophilic profile work-up was performed in each woman. Open biopsy from the lesions was taken from one of the women for histological sections and immunohistochemical stains.Results: Five women developed combined jugular and subclavian vein thrombosis following ART. They were found to harbor clusters of rudimentary branchial cysts filled with fluid at the time of ovarian hyperstimulation syndrome, which compressed the jugular and subclavian veins at their junction at the base of the neck. Four patients (80%) were found to be carriers of factor V Leiden.Conclusion: The predilection of combined jugular and subclavian vein thrombosis early in pregnancy is the result of mechanical compression mediated by rudimentary branchial cysts filled with fluid during ovarian hyperstimulation syndrome, particularly in subjects who are carriers of factor V Leiden.

Luteal estradiol patch/GnRH-antagonist suppression prior to gonadotropin stimulation in patients with elevated follicle stimulating hormone (FSH) levels

OBJECTIVE: Hormonal stimulation incorporating luteal estradiol patch and GnRH antagonist suppression followed by high dose gonadotropin stimulation has been shown to result in lower cancellation rates and satisfactory pregnancy rates for poor responders (Fertil Steril 2005). Subsequent experience has demonstrated the efficacy of this protocol. The purpose of this study was to analyze results specifically for patients with elevated FSH levels.

The clomiphene citrate challenge test (CCCT) in women with elevated basal FSH: Biological significance and predictive value

Objective The rationale of the clomiphene citrate challenge test (CCCT) is that day 10 serum FSH is influenced by the quality of the recruited oocytes. Biological evidence supporting this assumption is, however, lacking. The aim of this study is to investigate the relationship between results from the CCCT and the quantity and the quality of the recruited oocytes. Study design Patients selected for in vitro fertilization (IVF) and who were found to have elevated basal FSH ( n = 114) underwent an IVF cycle using follicles developing during CCCT. Subsequently, a subgroup of patients ( n = 89) underwent a second cycle receiving high doses of gonadotropins. The main outcome considered was the transfer of viable embryos. Results During the CCCT cycle, the area under the receiver operating characteristics (ROC) curves for day 3 and day 10 serum FSH to predict embryo-transfer was 0.48 (95% CI, 0.37–0.60) and 0.74 (95% CI, 0.63–0.82), respectively. In the subsequent cycle, the area under the ROC curves for the two variables was 0.58 (0.43–0.72) and 0.58 (0.43–0.72), respectively. Conclusions CCCT effectively mirrors the quantity and the quality of the recruited oocytes but its predictive value is low.

Poor responder protocols for in-vitro fertilization: options and results

To present the options and the results in the management of poor responders in in-vitro fertilization. There is no controlled ovarian hyperstimulation protocol which is best suited for all poor responders. Low dose gonadotropin-releasing hormone agonist regimes appear to be most advantageous. Prediction of compromised response prior to cycle initiation by a thorough assessment of ovarian reserve as well as a careful review of past responses could allow for a more appropriate selection of a controlled ovarian hyperstimulation protocol for each individual patient. Optimistic data have been presented by the use of high doses of gonadotropins, flare up gonadotropin-releasing hormone agonist protocols (standard or microdose), stop protocols, luteal onset of gonadotropin-releasing hormone agonist, and short protocols. Natural cycle also seems to be an appropriate strategy to be considered. There is no universal definition for the 'poor responder'. Numerous strategies have been proposed to improve ovarian stimulation in poor responders, but none of them is the ideal for all such patients. More data from good quality controlled trials are needed.

Growth hormone co-treatment within a GnRH agonist long protocol in patients with poor ovarian response: a prospective, randomized, clinical trial

The efficacy of growth hormone co-stimulation to long luteal GnRHa regimen in poor responders to COH for IVF was assessed. This prospective, randomized, clinical trial was performed in a private assisted reproduction center. The study involved 61 patients who responded poorly to high dose gonadotropin treatment in their first cycles in the same center. Study group of 31 patients were given growth hormone co-treatment, daily subcutaneous injection of 4 mg from day 21 of preceding cycle along with GnRHa, until the day of hCG. Control group of 30 patients received the same treatment protocol except the growth hormone cotreatment. Primary end-point of the study was the number of oocytes fertilized whereas the pregnancy rate was the secondary end-point. Patients' demographic characteristics did not differ significantly between the two groups. 2PNs in growth hormone co-treatment group was significantly higher than the control group (4.4 +/- 1.8 vs 1.5 +/- 0.9, p < 0.001). Although more pregnancies and more clinical pregnancies with fetal heart beat were achieved in growth hormone group (12/31), compared to the control group (6/30), the difference did not reach to statistical significance. Poor responder women undergoing repeated assisted reproduction treatment and co-stimulated with GH achieve more oocytes, higher fertilization rate if growth hormone started in the luteal phase of previous cycle, as compared with women of the same status treated with GnRHa long protocol. The study was unable to show that clinical pregnancy rate was increased significantly.

Prospective, randomized, comparative study of leuprorelin + human menopausal gonadotropins versus ganirelix + recombinant follicle-stimulating hormone in oocyte donors and pregnancy rates among the corresponding recipients

Aim. To compare the clinical pregnancy rate in recipients of oocytes from donors treated with leuprorelin + human menopausal gonadotropins (hMG) with that obtained when the donors were treated with ganirelix + recombinant follicle-stimulating hormone (rFSH). The secondary aim was to compare the donors' response to the two treatments.Method. A prospective, randomized, comparative study was conducted between January 2005 and November 2006 in a private hospital. Donors were randomized to receive a long protocol of leuprorelin + hMG (group DI) or ganirelix + rFSH (group DII). Their respective recipients were randomized to group RI or group RII, respectively.Results. The characteristics of the donors were similar in both groups. More cycles were cancelled in group DI than in group DII (28.1% vs. 2.5%; p < 0.05). Compared with donors in group DII, the donors in group DI required a significantly higher dose of gonadotropins (2794 ± 957 U vs. 1777 ± 1043 U; p < 0.05) and more days of stimulation (11.7 ± 2.3 vs. 9.5 ± 1.5; p < 0.05); they also yielded fewer oocytes (15.0 ± 6.1 vs. 17.9 ± 8.6; p < 0.05). There were no differences in the characteristics of the recipients, in the fertilization rate or in the number of embryos transferred. The quality of transferred embryos was better in group RI (8.0 ± 1.2 vs. 7.5 ± 1.6; p < 0.05), and this group also achieved a better pregnancy rate per embryo transfer than did group RII (62.3% vs. 48.4%; p < 0.05).Conclusions. Treating oocyte donors with leuprorelin + hMG produces among recipients a greater probability of clinical pregnancy per embryo transfer than when donors are treated with ganirelix + rFSH; however, more cycles are cancelled and the former treatment is more unpleasant for donors.

Different ovarian stimulation protocols for women with diminished ovarian reserve

To review the available treatments for women with significantly diminished ovarian reserve and assess the efficacy of different ovarian stimulation protocols. Literature research performed among studies that have been published in the Pubmed, in the Scopus Search Machine and in Cohrane database of systematic reviews. A lack of clear, uniform definition of the poor responders and a lack of large-scale randomized studies make data interpretation very difficult for precise conclusions. Optimistic data have been presented by the use of high doses of gonadotropins, flare up Gn RH-a protocol (standard or microdose), stop protocols, luteal onset of Gn RH-a and the short protocol. Natural cycle or a modified natural cycle seems to be an appropriate strategy. Low dose hCG in the first days of ovarian stimulation has promising results. Molecular biology tools (mutations, single nucleotide polymorphisms (SNPs)) have been also considered to assist the management of this group of patients. The ideal stimulation for these patients with diminished ovarian reserve remains a great challenge for the clinician, within the limits of our pharmaceutical quiver.

Features of follicle-stimulating hormone–stimulated follicles in a sheep model: keys to elucidate embryo failure in assisted reproductive technique cycles

To evaluate the individual functionality of gonadotropin-stimulated preovulatory follicles, for understanding embryo failure in assisted reproductive technique cycles, in a sheep model. Observational, model study. Public research unit. Fifteen adult Manchega ewes. Synchronization of the estrous cycle with intravaginal progestagens and ovarian stimulation with FSH; evaluation of reproductive activity, plasma sampling, ovarian ultrasonography, and ovariectomies. Determination of estrus behavior, plasma and intrafollicular concentrations of E(2) and inhibin A, number and size of ovarian follicles, and developmental competence of oocytes. These results support the usefulness of serial measurements of plasma inhibin A for assessment of follicular growth during the FSH treatment, rather than of E(2) assays commonly used. Functionality of FSH-stimulated preovulatory follicles is clearly disturbed, as confirmed by a negative correlation between follicular size and intrafollicular concentrations of inhibin A and E(2) in preovulatory follicles after individual dissection; moreover, the ability of their oocytes to resume meiosis was diminished. Functionality of follicles in controlled ovarian stimulation (COS), and developmental competence of their oocytes, is disturbed by the high doses of gonadotropin supplied and finally determined by follicular sizes at starting FSH treatment.

Early pregnancy loss in women stimulated with gonadotropin-releasing hormone antagonist protocols according to oral contraceptive pill pretreatment

To evaluate and compare the risk of early pregnancy loss in patients stimulated with GnRH antagonist protocols according to oral contraceptive pill (OCP) pretreatment. Retrospective case-control study. Instituto Valenciano de Infertilidad. University of Valencia. Spain. One thousand five hundred thirty-nine patients, aged <36, stimulated with GnRH antagonists for IVF between January 1, 2000 and November 1, 2005. Reproductive outcome was compared based on the application (or not) of OCP pretreatment: 944 women were included in the OCP group and 595 in the non-OCP group. The Student's t test was used for statistics. Pregnancy, biochemical pregnancy, ectopic pregnancy, early clinical pregnancy loss, early pregnancy loss, and ongoing pregnancy rates. No significant differences were observed in any of the outcome parameters. Early pregnancy loss rates were similar: 23% in the OCP pretreatment group versus 19.2% in the non-OCP pretreatment group. However, longer periods of ovarian stimulation and higher doses of gonadotropins needed to be employed in the OCP group. There is not sufficient evidence to confirm OCP pretreatment as a risk factor for miscarriage in patients stimulated with GnRH antagonist protocols.

Does previous response to clomifene citrate influence the selection of gonadotropin dosage given in subsequent superovulation treatment cycles?

To determine whether ovarian response to previous clomifene treatment could influence the selection of the starting dose of gonadotropins in subsequent in vitro fertilization (IVF) or intra uterine insemination (IUI). Forty three anovular women who had received clomifene for ovulation induction followed by gonadotropins for IUI or IVF superovulation were reviewed retrospectively. Data on gonadotropin dose were compared between clomifene-resistant patients and clomifene responders. IVF patients who had had prior superovulation/IUI treatment received similar doses of gonadotropins regardless of response to clomifene (1610 IU versus 1560 IU, p = 0.74). In IVF patients not receiving prior IUI treatment, the clomifene-resistant women were given higher doses of gonadotropins than those responding to clomifene (2500 IU versus 1440 IU, p = 0.042). We found that, in our Unit, clinicians appeared to use prior non-response to clomifene as a reason for prescribing a higher starting dose of gonadotropins in IVF treatment, a practice that is not evidence-based.

P-776: The search for an optimal stimulation protocol for intrauterine insemination (IUI): A Cochrane systematic review

Intrauterine insemination (IUI) combined with ovarian hyperstimulation (OH) has been proven an effective first-line treatment for subfertile couples but many different OH protocols using various drugs in various dosages have been compared with conflicting results, conclusions and guidelines for daily practice. For the first time all available evidence from randomized clinical trials (RCTs) comparing OH protocols for IUI has been collected and appraised following the guidelines of evidence based medicine as provided by the Cochrane collaboration. Cochrane systematic review using truly randomized clinical trials only. We performed an extensive search to detect all publications that described randomized trials comparing different OH protocols for IUI: We searched the Menstrual Disorders and Subfertility Group’s Central register of Controlled Trials (CENTRAL), the electronic databases of MEDLINE (1966 to present) and EMBASE (1980 to present). All trials were assessed by 2 independent reviewers for in-or exclusion and relevant data was extracted. Data was pooled into meta-analyses when appropriate. Pregnancy rate per couple was our primary outcome. Adverse outcomes such as multiple pregnancies and ovarian hyperstimulation syndrome (OHSS) were considered. 81 RCTs were found and 43 could be included in this review. Seven RCTs compared anti-estrogens with gonadotropins in an IUI program. After pooling a significant difference in favor of gonadotropins was found (OR 1.8, 95% CI 1.2 to 2.7). The number of multiple pregnancies per treatment modality did not differ significantly (OR 1.2 95% CI 0.3 to 5). Both the addition of a GnRH agonist (4 RCTs) as the addition of a GnRH antagonist (3 RCTs) did not show a significant difference in pregnancy rates compared to gonadotropins alone. However, GnRH antagonist showed a tendency to improve treatment outcome (OR 1.6 95% CI 0.9 to 2.8). The addition of a GnRH agonist resulted in significant higher multiple pregnancy rates (OR 4.5 95% CI 1.4 to 15). Furthermore, five RCTs compared aromatase-inhibitors with anti-estrogens. When pooling the results it showed no evidence of benefit using aromatase-inhibitors in IUI programs compared to anti-estrogens (OR 1.2 95% CI 0.6 to 2.1). Comparing 150 IU gonadotropins per day with 75 IU per day (2 RCTs) revealed no evidence of benefit using 150 IU gonadotropins per day (OR 1.2 95% CI 0.7 to 1.9). However, high dose gonadotropins resulted in significant more OHSS (OR 5.5 95% CI 1.9 to 17). Finally, 15 RCTs were included but did not provide the needed information about pregnancy rate per couple. This study demonstrates that gonadotropins are the most effective drugs for OH in IUI. Pregnancy rates with low dose gonadotropin protocols do not significantly differ from more aggressive stimulation protocols, but low dose gonadotropin protocols are associated with significantly fewer side effects. GnRH-agonists or aromatase-inhibitors do not improve treatment outcome. GnRH-antagonists show a tendency for higher pregnancy rates. In general, large cost-effectiveness trials using live birth rates as primary outcome are mandatory.

O-137: The quantitative and qualitative impact of gonadotropin stimulation on human preimplantation embryos: A preliminary study

Reported aneuploidy rates in infertile women, undergoing ovarian stimulation with gonadotropins, have uniformly been reported as high. Whether these rates are ”natural“, or are the consequence of gonadotropin stimulation is, however, unknown. This study, therefore, evaluates the qualitative and quantitative impact of controlled ovarian hyperstimulation with gonadotropins on euploidy rates in human cleavage-stage-embryos. Retrospective cohort study. 678 women with normal ovarian function (based on baseline FSH levels < 10mIU/ml), at ages 24-47 years, underwent, during IVF cycles, three different stimulation protocols, followed by preimplantation genetic diagnosis (PGD) for chromosomes X, Y, 13, 15, 16, 17, 18, 21 and 22. The utilized stimulation protocols involved (1) long agonist stimulation; (2) short agonist stimulation (i.e. a flare or microdose protocol); and (3) antagonist use and were allocated based on stimulation history or other clinical assumptions. Gonadotropin stimulation utilized rec. FSH and/or hMG at varying dosages. Patients underwent PGD for different reasons: Older patients for maternal age, younger patients because of prior implantation failure, patient preference, personal or religious concerns about an abnormal fetus or unwillingness to transfer more embryos. Total gonadotropin usage per cycle correlated positively with the absolute number of euploid embryos achieved per IVF cycle (p=0.03), but showed a negative correlation with the overall percentage of chromosomally normal embryos (p=0.02). LH-containing stimulation resulted in significantly increased percentages of euploid embryos (p=0.02), though in the presence of a decreased absolute number of embryos (p=0.02). When women were age stratified, the positive effect of LH-including stimulation on euploidy (i.e. percentage of euploid embryos) was exclusively present in younger women below age 37.5 years. (p=0.001) Long agonist protocols positively affected percentages of euploid embryos (p<0.0001) in comparison to the other two protocols utilized and this effect was statistically visible in younger as well as older women, below and above age 37.5 years (p<0.01) . This preliminary data set suggests that higher gonadotropin dosages result in more euploid embryos for transfer, even though they reduce the percentage of euploid embryos. High dose gonadotropin stimulation, resulting in large embryo numbers, may, therefore, represent a potential indication for PGD. Exogenous LH supplementation, especially in younger women, and long agonist protocols, appear to improve euploidy rates, though a patient selection bias in regards to the selection of stimulation protocols cannot be ruled out. Euploidy rates after ovarian stimulation thus appear quantitatively and qualitatively affected by stimulation protocols and medication dosages.

Elevated serum müllerian-inhibiting substance may be a marker for ovarian hyperstimulation syndrome in normal women undergoing in vitro fertilization

We identified patients who experienced ovarian hyperstimulation syndrome (OHSS) (n = 16) and compared their baseline pretreatment levels of müllerian-inhibiting substance (MIS) to age- and weight-matched patients with normal responses to gonadotropins (n = 14). Baseline serum MIS in patients with OHSS were sixfold higher than those seen in normal controls (3.62 +/- 0.87 vs. 0.63 +/- 0.09 ng/mL; P=.0036), indicating that MIS could potentially serve as a useful marker for identifying patients at risk for OHSS.

Clinical Efficacy of Body Mass Index as Predictor of In Vitro Fertilization and Embryo Transfer Outcomes

The aim of this study was to evaluate the clinical efficacy of body mass index (BMI) as a predictor of in vitro fertilization and embryo transfer (IVF-ET) outcomes. Two hundred twenty-three IVF-ET cycles in 164 patients under 37 yr using GnRH agonist long protocols were included in this retrospective study. All of the selected cases were divided into two groups by a cutoff of 24 kg/m2 and these two groups were compared in regard to the outcomes of IVF-ET. There were no significant differences between group 1 (BMI <24 kg/m2) and group 2 (BMI ≥ 24 kg/m2) in age, basal serum FSH level, estradiol (E2) level and endometrial thickness on hCG day, number of retrieved oocytes and transferred embryos. However, higher doses of gonadotropins were used in group 2 (30.8±12.7 ampoules vs. 35.4±15.3 ampoules, p=0.051). The clinical pregnancy rate was significantly lower in group 2 (25.9% vs. 10.5%, p=0.041) and implantation rate tended to be lower in group 2 (12.7% vs. 6.8%, p=0.085). BMI ≥ 24 kg/m2 can be a candidate prognosticator of IVF-ET outcomes.

What is the underlying cause of aneuploidy associated with increasing maternal age? Is it associated with elevated levels of gonadotropins?

Aneuploidy is the most common chromosomal abnormality and also is the leading cause of early fetal loss and serious mental retardations. Except for the advanced maternal age, there is no clearly established factor for the development of aneuploidy. On the other hand, advanced maternal age is well characterized with elevated gonadotropin levels due to the decreased ovarian reserve. Such high level gonadotropins are also seen physiologically in the adolescent period. Both age groups may have an increased risk for having a baby with chromosomal abnormality. On the other hand, high doses of gonadotropins are widely used in artificial reproductive technologies (ART). Low pregnancy and high abortion rates in ART practices may be explained by higher incidence of chromosomal abnormalities in the unfertilized oocytes maturated by high dose gonadotropins. Gonadotropins are also found to induce congenital malformations and chromosomal abnormalities in some animal studies. From this point of view, we hypothesized that gonadotropins might have a role in the development of aneuploidy. If this hypothesis is true, basal serum FSH levels may be used as a screening test in preconceptional period for assessment of the aneuploidy risk in low risk population. Furthermore, new ART protocols using low dose gonadotropins should be developed in order to improve pregnancy outcomes and possibly to prevent aneuploidy.

Diminishing Returns of Increasing Gonadotropin Dosage in Subsequent In Vitro Fertilization (IVF) Cycles?

IVF success is related to the number of mature oocytes retrieved. In some patients, despite high dose gonadotropin (Gn) stimulation, few oocytes are retrieved and few quality embryos are available for transfer. The goal of this study is to assess the result of increasing Gn dosage on subsequent IVF cycles.

Using the Antagonist Cetrotide 3 mg in the Luteal Phase Prior to IVF Stimulation Results in a Improved IVF Cycle Outcomes in Poor Responders and Decreased Ovarian Reserve Patients

Background: For many patients with high basal FSH or estradiol levels and/or patients with poor responses to gonadotropin stimulation for IVF, identifying an appropriate protocol to achieve an adequate response can be a challenge. Many low responders will stimulate very quickly to high doses of gonadotropins and make few mature follicles or have significant asynchrony in follicle sizes, especially in microdose Lupron protocols. Endogenous late luteal phase FSH levels may drive this asynchrony as well.

Elevated temperature (heat stress) in vitro reduces androstenedione and estradiol and increases progesterone secretion by follicular cells from bovine dominant follicles

Dairy cattle are susceptible to heat stress-induced reductions in fertility; however, direct effects of hyperthermia on specific reproductive functions are difficult to determine in vivo. The objective of this experiment was to examine the effect of elevated temperature in vitro on follicular steroidogenesis, to gain insight into specific follicular responses associated with heat stress. Dominant follicles were obtained from Holstein heifers on day 6 post-estrus (luteal phase; n = 4) or day 8, 36 h after an injection with 25 mg PGF 2α to induce regression of the corpus luteum (follicular phase; n = 4). Pieces of follicle wall were isolated from dominant follicles and cultured for 96 h with 0, 2 or 100 ng/ml LH or FSH at 37, 39 or 41 °C. Concentrations of androstenedione, estradiol and progesterone were determined in culture media collected every 24 h. During the last 48 h of culture, basal secretion of androstenedione and estradiol by pieces of follicle wall was lower at 41 °C than at 37 or 39 °C ( P < 0.05). In contrast, cumulative secretion of progesterone by pieces of follicle wall in medium alone was higher at 41 °C than at 37 or 39 °C ( P < 0.05). Pieces of follicle wall responded to treatment with both low (2 ng/ml) and high (100 ng/ml) doses of gonadotropins at all temperatures. However, gonadotropin-induced secretion of androstenedione and estradiol was generally lower, whereas gonadotropin-induced secretion of progesterone was higher at 41 °C and sometimes at 39 than at 37 °C. The changes in basal steroidogenesis and in responses to gonadotropins suggest that follicular cells begin to luteinize at elevated temperatures in vitro. Premature luteinization of follicular cells in vivo has been associated with reduced fertility in cattle with persistent follicles, suggesting that the premature differentiation of follicular cells observed in the current study may be responsible, in part, for the reduced fertility of dairy cattle under heat-stressed conditions.