Multi-centre phase IV trial to investigate the immunogenicity of a new liquid formulation of recombinant human growth hormone in adults with growth hormone deficiency.

PURPOSE: To investigate whether a new liquid formulation of recombinant human growth hormone (r-hGH) induces the production of binding antibodies (BAbs) in adults with congenital or adult-onset growth hormone deficiency (GHD). METHODS: Men or women aged 19-65 years with adult growth hormone deficiency who were r-hGH-naïve or had stopped treatment ≥ 1 month before screening were treated with between 0.15 and 0.30 mg/day r-hGH liquid formulation for 39 weeks. The primary endpoint was the proportion of patients who developed BAbs at any time. Secondary endpoints were the proportion of patients with BAbs who became positive for neutralising antibodies, the effects on biomarkers of r-hGH exposure, safety, and adherence to treatment downloaded from the easypod™ connect software. RESULTS: Seventy-eight patients (61.5% men) with mean age 44.5 years (range 21-65) started and 68 (87.2%) completed the 39-week treatment period. 82.1% were treatment naïve; all were negative for BAbs to r-hGH at baseline. The median (interquartile range) duration of treatment [273 (267.0-277.0) days] was consistent with patients receiving the required doses, and mean treatment adherence measured using easypod™ connect was 89.3%. The proportion of patients who developed BAbs was 0% (95% confidence interval 0-4.68%) and biomarker profiles were consistent with exposure to r-hGH. 92.3% of patients reported ≥ 1 adverse event during treatment. Most events were mild or moderate and no new safety concerns were detected. CONCLUSIONS: The low immunogenicity profile of the liquid formulation was consistent with that for the freeze-dried formulation, and no new safety concerns were reported.

Individualizing FSH dose for assisted reproduction using a novel algorithm: the CONSORT study.

The CONSORT dosing algorithm individualizes recombinant human FSH (r-hFSH) doses for assisted reproduction technologies, assigning 37.5 IU increments according to patient characteristics: basal FSH, body mass index, age and antral follicle count. A prospective, uncontrolled, international, 18-centre, pilot study of normo-ovulatory women aged 18-34 years inclusive undergoing a long agonist treatment protocol was performed. Follitropin alfa filled-by-mass (GONAL-f®) dose was assigned by the algorithm and was intended to be altered only for risk of ovarian hyperstimulation syndrome (OHSS). Primary end-point was number of oocytes retrieved. Dose groups containing ≥5 patients were analysed: 75 IU (n = 48), 112.5 IU in = 45), 150 IU (n = 34), 187.5 IU (n = 24), 225 IU (n = 10). Cancellations due to inadequate response were higher than expected in the 75 IU group (12/48). Overall, a median of 9.0 oocytes were retrieved (8.5, 8.0, 10.0, 12.0 and 8.0 in the 75, 112.5, 150, 187.5 and 225 IU groups respectively). Clinical pregnancy rates/cycle started were 31.3, 31.1, 35.3, 50.0 and 20.0%, respectively (overall, 34.2%). Two patients had severe OHSS. Use of the CONSORT algorithm achieved an adequate oocyte yield and good pregnancy rates in this preliminary study. Adjustment of the algorithm could reduce cancellation rates.

Factors related to successful ovulation induction in patients with WHO group II anovulatory infertility.

To identify baseline characteristics related to successful ovulation induction, data were analysed from oligo- or anovulatory patients undergoing their first cycle of human recombinant FSH (r-hFSH; follitropin alfa) in a chronic low-dose (75 IU starting dose), step-up protocol in two clinical trials (n=446). Patients were grouped according to response: group A, ovulated within 14 days (75 IU follitropin alfa); group B, ovulated after 14 days (>75 IU follitropin alfa); group C, not administered human chorionic gonadotrophin (HCG) because of poor response; group D, cycle cancelled due to over-response (HCG not administered); group E, spontaneous ovulation prior to obtaining criteria for administration of HCG. Mean body mass index (BMI) of group A (25.0 kg/m(2)) was significantly lower than groups B (27.1 kg/m(2), P<0.001) or C (28.2 kg/m(2), P<0.0001), but similar to group D (24.3 kg/m(2)). Mean antral follicle count (AFC) of group A was also significantly lower than group C (18.3 versus 22.7; P=0.018), but not significantly different from groups B (21.5) or D (19.5); group E had the highest mean AFC (35.7). Comparatively low BMI, low AFC and higher (although still within the normal range) FSH concentration at baseline were associated with successful ovulation induction in infertile women undergoing a chronic low-dose, step-up stimulation protocol.

Individualizing FSH dose for assisted reproduction using a novel algorithm: the CONSORT study.

The CONSORT dosing algorithm individualizes recombinant human FSH (r-hFSH) doses for assisted reproduction technologies, assigning 37.5 IU increments according to patient characteristics: basal FSH, body mass index, age and antral follicle count. A prospective, uncontrolled, international, 18-centre, pilot study of normo-ovulatory women aged 18-34 years inclusive undergoing a long agonist treatment protocol was performed. Follitropin alpha filled-by-mass (GONAL-f) dose was assigned by the algorithm and was intended to be altered only for risk of ovarian hyperstimulation syndrome (OHSS). Primary end-point was number of oocytes retrieved. Dose groups containing >or=5 patients were analysed: 75 IU (n = 48), 112.5 IU (n = 45), 150 IU (n = 34), 187.5 IU (n = 24), 225 IU (n = 10). Cancellations due to inadequate response were higher than expected in the 75 IU group (12/48). Overall, a median of 9.0 oocytes were retrieved (8.5, 8.0, 10.0, 12.0 and 8.0 in the 75, 112.5, 150, 187.5 and 225 IU groups respectively). Clinical pregnancy rates/cycle started were 31.3, 31.1, 35.3, 50.0 and 20.0%, respectively (overall, 34.2%). Two patients had severe OHSS. Use of the CONSORT algorithm achieved an adequate oocyte yield and good pregnancy rates in this preliminary study. Adjustment of the algorithm could reduce cancellation rates.

Predictive factors and a corresponding treatment algorithm for controlled ovarian stimulation in patients treated with recombinant human follicle stimulating hormone (follitropin alfa) during assisted reproduction technology (ART) procedures. An analysis of 1378 patients.

BACKGROUND: Identifying parameters that can accurately predict the response to controlled ovarian stimulation (COS) would be of great benefit in assisted reproductive technology (ART) procedures. An analysis was undertaken with the objective of determining whether specific factors could optimally predict a response to stimulation in ART, and to then develop a corresponding treatment algorithm that could be used to calculate the optimal starting dose of recombinant human follicle stimulating hormone (r-hFSH; follitropin alfa) for selected patients. METHODS: The overall population consisted of 2280 normo-ovulatory ART patients from 11 randomised clinical trials. However, for the final analysis population, only patients less than 35 years of age who received r-hFSH monotherapy (N = 1378) were included. RESULTS: Backwards stepwise regression modelling indicated that predictive factors for ovarian response included basal FSH, BMI, age and number of follicles < 11 mm at baseline screening. The concordance probability index was 59.5% for this model. CONCLUSIONS: In the largest data series so far analysed to determine predictive factors of ovarian response, basal FSH, BMI, age and number of follicles < 11 mm at screening were the most important variables in ART patients less than 35 years of age who were treated with r-hFSH monotherapy. Using these four predictive factors, a follitropin alfa starting dose calculator was developed that can be used to select the FSH starting dose required for an optimal response. The relevance of this dose calculator will be evaluated in a prospective clinical trial.

Clinical management of functional ovarian cysts: a prospective and randomized study.

Most ovarian cysts in women of reproductive age are physiological (functional) and patients have been treated for years with oral contraceptives to obtain the resolution of these cysts. Expectant management has been suggested to have the same effectiveness as hormonal treatment but such suggestions come from studies including all kinds of cysts. The objective of the present study was to assess the resolution of functional ovarian cysts, observed after ovulation induction, with expectant management and hormonal treatment and also to determine the period of time necessary for the resolution of the cysts. For this purpose, 53 patients with ovarian cysts, observed by transvaginal ultrasound within the first 5 days of a cycle after ovulation induction, were randomized to have expectant management (group A) or to receive oral contraception (group B) for one cycle. If the cyst persisted, the patient was followed for another cycle, without any treatment. Within the 50 women who completed the trial, a complete resolution of the cysts was observed in 19/25 (76%) and 18/25 (72%) in groups A and B respectively. On the other hand, all the persistent cysts disappeared after a second cycle without any treatment. In conclusion, expectant management is as effective as oral contraceptives for the resolution of functional ovarian cysts induced by ovarian stimulation. However, studies with a larger number of cases are needed to increase the power of the results and to obtain a firm conclusion.

Prospective randomized trial to evaluate the efficacy of a vaginal ring releasing progesterone for IVF and oocyte donation.

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.

Preliminary results on the role of embryonic human chorionic gonadotrophin in corpus luteum rescue during early pregnancy and the relationship to abortion and ectopic pregnancy.

The precise mechanisms by which corpus luteum (CL) function is modulated during early pregnancy are not known. Evidence in failed pregnancies (ectopic, abortions), shows that factors other than human chorionic gonadotrophin (HCG) could be involved in its regulation. The objective of this study was to investigate the dynamics of beta-HCG, progesterone and oestradiol production in early pregnancy and its relation to embryonic quality and topographic localization. Plasma concentrations of progesterone, oestradiol and beta-HCG were studied between days +12 and +21 after an in-vitro fertilization (IVF) embryo transfer in 11 intrauterine pregnancies, 10 intrauterine abortions and seven tubal pregnancies. Tubal pregnancies and abortions were grouped according to doubling time (DT) of HCG. Results showed that oestradiol concentrations were apparently reduced in both ectopic pregnancies and abortions compared with normal pregnancies. The fall in oestradiol concentrations was seen in ectopic pregnancies with an abnormal DT for HCG and in all abortions. When the ectopic pregnancy had a normal DT, oestradiol and progesterone concentrations were normal. In abortions, the fall in oestradiol and progesterone concentrations was less influenced by the DT of HCG. These findings suggest that corpus luteum function depends on an adequate DT of HCG more than an absolute value, and with normal trophoblastic tissue the site of implantation does not affect CL function.

Comparison of ultrasonography and hysteroscopy in the diagnosis of intrauterine lesions in infertile women.

STUDY OBJECTIVE: To compare the effectiveness of transvaginal ultrasound versus hysteroscopy in the diagnosis of benign intrauterine lesions, with histology as the gold standard. DESIGN: Retrospective study (Canadian Task Force classification II-1). SETTING: Unit of Reproductive Medicine, Department of Obstetrics and Gynecology of Clinica Las Condes, Santiago, Chile. PATIENTS: Infertile women who had undergone complete fertility evaluation. INTERVENTION: Transvaginal ultrasound, hysteroscopy, and histologic evaluation of endometrial samples performed in all 126 women. MEASUREMENTS AND MAIN RESULTS: The most frequent condition was a normal cavity (59.5%), followed by endometrial polyps (34.9%) and fibromyomas (3.9%). Synechiae and bone metaplasia were extremely rare. Sensitivity of transvaginal ultrasound for the diagnosis of endometrial polyps was 95.6% compared with 89.9% for hysteroscopy (NS). Specificity was 97.4% with transvaginal ultrasound versus 93. 3% with hysteroscopy (NS). Positive and negative predictive values were similar for both methods. CONCLUSION: Transvaginal ultrasound is as effective as hysteroscopy in diagnosing benign intrauterine lesions. It could be the first clinical diagnostic test in the investigation of the uterine cavity.

Comparison of Ultrasonography and Hysteroscopy in the Diagnosis of Intrauterine Lesions in Infertile Women

Transvaginal ultrasound is a noninvasive diagnostic technique that remains to be proved as accurate as hysteroscopy in the diagnosis of benign intrauterine lesions. We compared its efficacy with that of hysteroscopy in the diagnosis of benign intrauterine pathology in 126 infertile women in whom the diagnosis was confirmed by histologic studies. The women had a complete evaluation with preoperative transvaginal ultrasound, hysteroscopy, and histologic analysis of uterine cavity specimens. Sensivity, specificity, and predictive values were calculated for ultrasound and hysteroscopy considering the histologic study as 100%. Sensivity was 95% and 100%, and specificity 97.4% and 93.7% for transvaginal ultrasound and hysteroscopy, respectively. The positive predictive value for benign intrauterine lesions was 100% for ultrasound and 89.8% for hysteroscopy. The most frequent intrauterine lesions found were polyps and myomas. Transvaginal ultrasound is a valuable method of diagnosing benign intrauterine lesions in infertile women, and is especially important as a noninvasive technique to plan hysteroscopic surgery.

Hysteroscopic Correction of Cesarean Section Scars in Women with Abnormal Uterine Bleeding

Abnormal postmenstrual uterine bleeding may occur in women with history of cesarean section. To study the etiology of this anomaly, transvaginal ultrasound (TVU) was performed during follicular phase in 20 such patients, and hysteroscopy in 7. The TVU revealed the presence of fluid in the isthmus in relation to the cesarean section scar, where a kind of pouch or bursa was observed. Cervical introduction of a catheter showed that the fluid was blood. The TVU observation was confirmed in women in whom hysteroscopy was performed. Resection of ring-shaped fibrotic tissue on the inferior part of the scar stopped abnormal bleeding. Four women were infertile and two conceived, probably because stopping postmenstrual bleeding could interfere with the quality of cervical mucus. These findings suggest that abnormal uterine bleeding in women with an abnormal uterine scar could be resolved by minimally invasive endoscopic surgery, and TVU is a valuable diagnostic tool.

The abnormally large follicle during controlled ovarian hyperstimulation: management and outcome of the cycle.

OBJECTIVE: To investigate if the presence of an abnormally large follicle during controlled ovarian hyperstimulation (COH) under pituitary suppression has any effect on the outcome of the cycle. DESIGN: Prospective, observational. SETTING: The reproductive endocrinology unit of a university hospital. PATIENTS: One hundred fifty patients undergoing COH for assisted reproductive techniques during a 6-month period (August 1990 to January 1991). INTERVENTIONS: Transvaginal follicular aspiration and IVF-uterine ET. RESULTS: A total of 19 cycles had abnormally large follicles identified on day 8 of the stimulation cycle after normal baseline ultrasound. Gonadotropins were continued and hCG injection was indicated when two or more follicles of the main cohort achieved a diameter of 20 to 22 mm. Twenty preovulatory oocytes were retrieved from 22 large follicles. Two were transferred for GIFT and 18 were inseminated in vitro, resulting in a 72.0% fertilization rate. The mean number of oocytes retrieved per patient was 10.9, 71.4% of which were mature with a fertilization rate of 67.7%. All these figures were comparable with the results obtained in the 131 patients of the control group undergoing IVF. No evidence of premature luteinization was observed in the study group, based on plasma P levels (x 0.83 ng/mL [conversion factor to SI unit, 3.180], range 0.31 to 1.40 ng/mL). The clinical pregnancy rate for the group with abnormally large follicles did not differ from the control group (27.8% versus 28.2%, respectively). CONCLUSIONS: The presence of an abnormally large follicle during COH under pituitary suppression does not affect the outcome of the cycle. Moreover, under these conditions, continuous gonadotropin stimulation of a follicle to diameters considerably larger than the standard ones does not have a detrimental effect on the oocyte contained in it, suggesting that oocyte aging is an independent process from follicular growth once LH surge is prevented.

[Follicular and endometrial growth profiles in stimulated cycles with clomiphene citrate]. / Perfil de crecimiento folicular y endometrial en ciclos estimulados con citrato de clomifeno.

To study follicular and endometrial growth patterns in Clomiphene Citrate (CC) stimulated cycles, 50 CC cycles of 31 infertile women with patient Fallopian Tubes, were followed, 17 spontaneous conceptional cycles of fertile women were followed as controls. The pattern of follicular growth was similar in both groups until the day before ovulation in which CC cycles showed larger follicular diameters than spontaneous ones; 23.8 +/- 3.1 mm versus 21.6 +/- 2.9 mm (p = 0.013). Follicular rupture occurred on day 16.1 +/- 2.9 in CC cycles, and on day 15.1 +/- 1.85 on spontaneous conceptional ones. This suggests that the follicle, under the influence of CC, has to reach a larger critical mass to produce enough estradiol to revert the hypothalamic blockage produced by the drug, thus permitting the preovulatory LH surge. Endometrium under CC action, was always thinner than in natural cycles. On the day of follicular rupture, the CC cycle's endometrium measured 11.1 +/- 2.02 mm and the natural cycle's endometrium measured 10.6 +/- 1.8 mm (ns). This finding could be attributed to a antiestrogenic effect of CC on the endometrium. It is concluded that cycles under CC action have different follicular and endometrial growth patterns than spontaneous conceptional cycles.

Pregnancy and implantation rates in normal replacement versus stimulated cycles.

The relative importance that endometrial development and embryo quality have on implantation rates achieved with assisted reproductive technology (ART) is the subject of controversy. Ovarian stimulation has been repeatedly mentioned as having a detrimental effect on endometrial receptivity (Paulson et al., 1990, Fertil. Steril., 53, 870-874). We compared pregnancy and implantation rates achieved with ART during stimulated cycles and hormonal replacement cycles, in patients matched for the following criteria: age < 35 years for the patient donating oocytes; transfer of at least two good quality embryos/oocytes and good quality transfer. All transfer cases performed during hormonal replacement cycles were done with donated oocytes. Comparison of results between techniques was not attempted due to potential differences in populations. The pregnancy and implantation rates achieved with each technique during stimulated and hormonal replacement cycles were not statistically different. In contradiction to previous results, our data suggest that differences in uterine receptivity between stimulated and hormonal replacement cycles in the age group studied are not of critical importance in embryo implantation. Good embryo quality appears to be the dominant factor in determining the success of ART.

Cumulative pregnancy rate from one gamete intra-fallopian transfer (GIFT) cycle with cryopreservation of embryos: a practical mathematical calculation.

We evaluated the cumulative pregnancy rate from one gamete intra-Fallopian transfer (GIFT) cycle plus subsequent cycles in which embryos cryopreserved at the time of the original GIFT cycle were transferred. All patients who had their first GIFT cycle in our centre between January, 1989 and March, 1991 were included. Ovarian stimulation was accomplished with leuprolide acetate (luteal phase protocol) and a combination of follicle stimulating hormone and human menopausal gonadotrophin. GIFT was performed with three to five oocytes. Excess oocytes were inseminated and good quality embryos were cryopreserved at the 2- to 4-cell stage with 1-2 propanediol. When the GIFT cycle did not result in a pregnancy, uterine transfer of cryopreserved embryos was carried out in subsequent unstimulated cycles. A total of 97 patients had GIFT and 46 pregnancies were achieved (47.4%). A total of 51 patients (52.5%) had embryos frozen; of these, 21 were from the non-pregnant group (41.1%) and 30 from the pregnant group (65.2%) (P < 0.05). Up to now, 22 of them have undergone a frozen-thawed embryo transfer cycle, and two of them achieved a pregnancy. Based on these data, patients having a GIFT could theoretically expect a cumulative pregnancy rate of 52.2%.

[Simplified management of an in vitro fertilization program]. / Manejo simplificado de un programa de fertilización in vitro.

The development of in vitro fertilization has accelerated in a dramatic way the understanding on gamete physiology. Results obtained with the technique are easily reproducible and consistent between different centers. It is well known that cumulative pregnancy rates with 5 or 6 cycles can reach up to 60% of couples being pregnant. However, the main limitations to successive attempts have been the cost of the procedure and the surgical transfer of the embryos. In an attempt to overcome this difficulties, efforts has been made to simplify the monitoring of induction of ovulation, use of GnRh analogs and non surgical transfers whenever it is possible. Results presented in 47 of these cycles show non significant differences, with data published elsewhere, on oocyte maturity, fertilization and cleavage rates. Moreover pregnancy rates per aspiration are 28.6% and per transfer 33.3%. We can conclude that ultrasonography alone to monitor ovulation induction as well as uterine transfers do not affect the outcome of the cycle.

Embryo implantation rates in oocyte donation: a prospective comparison of tubal versus uterine transfers.

OBJECTIVE: To compare pregnancy and implantation rates in tubal and uterine transfers during a hormonal replacement cycle in an oocyte donation program. DESIGN: Prospective randomized. PATIENTS: Forty-two consecutive patients who entered an oocyte donation program. INTERVENTIONS: Twenty-two patients were assigned for uterine transfer and 20 for tubal embryo transfer (ET). RESULTS: Twenty-three pregnancies were achieved, 12 (54.5%) after uterine transfers and 11 (57.9%) after tubal transfers. Implantation rates in both groups are not significantly different (17.4% uterine transfers versus 21.5% tubal ETs). CONCLUSIONS: Our results suggest that in hormonal replacement cycles (uniform endometrial stimulation) there is no advantage in transferring embryos to the fallopian tube. Furthermore, embryo quality and endometrial receptivity appear to be significantly more important than the time of entrance of an embryo to the uterine cavity in determining its chances of implantation.