Per Emil Rasmussen

Human menopausal gonadotropin versus recombinant follicle-stimulating hormone in normogonadotropic women down-regulated with a gonadotropin-releasing hormone agonist who were undergoing in vitro fertilization and intracytoplasmic sperm injection: a prospective randomized study

OBJECTIVE To evaluate clinical and endocrinological effects of intranasal (IN) vs. subcutaneous (SC) GnRH-a for pituitary down-regulation combined with hMG vs. rFSH. DESIGN Prospective, randomized study. SETTING University hospital, IVF unit. PATIENT(S) Three hundred seventy-nine normogonadotropic women eligible for IVF or ICSI. INTERVENTION(S) Randomization to intranasal (IN) or SC GnRH-a and to hMG or rFSH. MAIN OUTCOME MEASURE(S) Oocytes retrieved, embryos developed, clinical pregnancy, and delivery rates. Serum hormone concentrations on stimulation days 1 (S1) and 8 (S8), and oocyte pick-up (OPU) day. RESULT(S) After randomization, four groups were formed: IN/hMG (n = 100), IN/FSH (n = 98), SC/hMG (n = 89), and SC/FSH (n = 92). Mean number of oocytes retrieved and of transferable and transferred embryos were similar in the four groups. Clinical pregnancy rate per started cycle was significantly higher in the IN/HMG group than in the SC/FSH group (P<.05) and was intermediate in the two remaining groups. Se-LH on S8 in the two SC groups was significantly lower than in the two IN groups. Se-E2 on S8 in the SC/FSH group was significantly lower than in the other three groups. CONCLUSION(S) The clinical and endocrinological outcome in IVF and ICSI-treated normogonadotropic women is significantly influenced by mode of down-regulation as well as gonadotropin formulation.

Homologous intrauterine insemination. An evaluation of prognostic factors based on a review of 2473 cycles

Objective. To identify prognostic factors influencing the outcome of infertility treatment using homologous intrauterine inseminations (IUI‐H).

Cryopreservation of ovarian tissue for a decade in Denmark: a view of the technique.

This paper presents the Danish 10-year experience (1999-2009) with cryopreservation (n=386) and autotransplantation of ovarian tissue (n=18). Before applying the technique to humans, the method was thoroughly tested and validated. The cryoprotectant solution was chosen after histological evaluation of mouse and human ovarian tissue after freezing with four different combinations of cryoprotectants. Viability was confirmed by transplantation of frozen-thawed human ovarian tissue (n=49) to oophorectomized Nude mice. Viability after transport of fresh tissue 4-5h prior to freezing had previously been validated. Overnight transport of fresh ovarian tissue prior to cryopreservation was evaluated when human ovarian tissue was kept on ice for 20h and then cryopreserved. The thawed ovarian tissue was transplanted to an oophorectomized Nude mouse and histology confirmed viability. In Denmark 12 women have received a total of 18 autotransplantations of ovarian tissue. All women resumed ovarian function and three healthy babies were born to two women. In both women, the tissue was transported on ice for 4-5h prior to cryopreservation. Ovarian tissue cryopreservation is an important method for fertility preservation; however, before applying the method clinically, each laboratory should perform thorough validation of their technique.

Cryopreservation of ovarian tissue for fertility preservation: no evidence of malignant cell contamination in ovarian tissue from patients with breast cancer

Cryopreserved ovarian cortical biopsies from 51 patients with breast cancer were examined by histologic and immunohistochemical analysis and showed no sign of metastases. Autotransplantation of ovarian cortex to patients with low-stage breast cancer disease appears safe, but confirmatory studies are required, including xenotransplantation studies.

Use of metformin before and during assisted reproductive technology in non-obese young infertile women with polycystic ovary syndrome: a prospective, randomized, double-blind, multi-centre study

BACKGROUND To study the effect of metformin before and during assisted reproductive technology (ART) on the clinical pregnancy rate (CPR) in non-obese women with polycystic ovary syndrome (PCOS). METHODS A multi-centre, prospective, randomized, double-blind study was conducted in eight IVF clinics in four Nordic countries. We enrolled 150 PCOS women with a body mass index <28 kg/m(2), and treated them with 2000 mg/day metformin or identical placebo tablets for ≥ 12 weeks prior to and during long protocol IVF or ICSI and until the day of pregnancy testing. The primary outcome measure was CPR. Secondary outcome measures included spontaneous pregnancy rates during the pretreatment period, and the live birth rate (LBR). RESULTS Among IVF treated women (n = 112), biochemical pregnancy rates were identical in both groups (42.9%), and there were no significant differences in the metformin versus the placebo group in CPR [39.3 versus 30.4%; 95% confidence interval (CI): -8.6 to 26.5]. The LBR was 37.5 versus 28.6% (95% CI: -8.4 to 26.3). However, prior to IVF there were 15 (20.3%) spontaneous pregnancies in the metformin group and eight (10.7%) in the placebo group (95% CI: -1.9 to 21.1; P = 0.1047). According to intention to treat analyses (n = 149); significantly higher overall CPR were observed in the metformin versus placebo group (50.0 versus 33.3%; 95% CI: -1.1 to 32.3; P = 0.0391). LBR was also significantly higher with use of metformin versus placebo (48.6 versus 32.0; 95% CI: 1.1 to 32.2; P = 0.0383). No major unexpected safety issues or multiple births were reported. More gastrointestinal side effects occurred in the metformin group (41 versus 12%; 95% CI: 0.15 to 0.42; P < 0.001). CONCLUSIONS Metformin treatment for 12 weeks before and during IVF or ICSI in non-obese women with PCOS significantly increases pregnancy and LBRs compared with placebo. However, there was no effect on the outcome of ART per se. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT00159575.

Intrauterine insemination with donor semen. An evaluation of prognostic factors based on a review of 1131 cycles

Objective. To identify prognostic factors influencing the outcome of infertility treatment using intrauterine insemination with donor semen (IUI‐D).

True ovarian volume is underestimated by two-dimensional transvaginal ultrasound measurement

OBJECTIVE To investigate a possible difference between true ovarian volume and ovarian volume estimated with two-dimensional (2D) transvaginal ultrasound. DESIGN Prospective clinical and laboratory study. SETTING University hospital research laboratory. PATIENT(S) Premenopausal girls and women from three Danish national fertility centers (A: n = 42; B: n = 6; C: n = 18), who had one entire ovary removed for cryopreservation of ovarian cortex. INTERVENTION(S) Transvaginal 2D ultrasound measurement of ovarian volume before oophorectomy. True ovarian volume was obtained by weighing the ovary. MAIN OUTCOME MEASURE(S) Ovarian volume estimated by weight and ultrasound. RESULT(S) Ovarian tissue density was 1.00 g/mL. Mean ovarian volume by ultrasound vs. weight in the three groups was as follows: A: 6.3 mL vs. 7.8 mL; B: 5.4 mL vs. 6.8 mL; and C: 2.8 mL vs. 6.1 ml. Ovarian volume obtained by ultrasound was at least 27% smaller than the true ovarian volume. CONCLUSION(S) Ovarian volume was severely underestimated by transvaginal 2D ultrasound measurement.

Concentrations of gonadotrophins and steroids in pre-ovulatory follicular fluid and serum in relation to stimulation protocol and outcome of assisted reproduction treatment

In this prospective, randomized study, concentrations of gonadotrophins and steroids in pre-ovulatory follicular fluid (FF) and serum were related to type of stimulation protocol as well as to the outcome of assisted reproduction in 280 women subjected to the long protocol gonadotrophin-releasing hormone (GnRH) agonist pituitary down-regulation and ovarian stimulation with either human menopausal gonadotrophin (HMG) or recombinant FSH. In the women treated with HMG, concentrations of LH, FSH, oestradiol and androstenedione in FF were significantly higher, and those of human chorionic gonadotrophin (HCG) and progesterone significantly lower, than in the women treated with recombinant FSH (rFSH). More women became pregnant and delivered in the HMG than in the rFSH group. These differences, however, were not statistically significant. Concentrations of FSH in serum and of FSH and LH in FF were significantly higher in conception than in non-conception cycles, whereas all other hormone concentrations in FF and serum were similar. The present study demonstrates that the pre-ovulatory follicular fluid hormone profile is significantly influenced by the gonadotrophin preparation used for ovarian stimulation, and suggests that ovarian stimulation with HMG results in an intra-follicular hormone profile more similar to that characterizing conception cycles than stimulation with rFSH. However, as the present data represent means of FF hormone profiles, they do not allow the conclusion of a direct correlation between the intra-follicular concentration of a certain hormone and the ability of the corresponding embryo to implant and establish an ongoing pregnancy.

Placental protein 14 concentrations in circulation related to hormonal parameters and reproductive outcome in women undergoing IVF/ICSI

Serum concentrations of placental protein 14 (PP14), steroids and gonadotrophins were related to the outcome of IVF/intracytoplasmic sperm injection in 195 normogonadotrophic women subjected to the long protocol gonadotrophin-releasing hormone agonist (GnRHa; buserelin) pituitary down-regulation protocol and gonadotrophin stimulation (HMG or rFSH). Pituitary down-regulation was initiated on cycle day 21 and the patients were randomized to either intranasal or s.c. administration of buserelin. After 14 days of down-regulation, the patients were randomized on stimulation day 1 (S1) to ovarian stimulation with 225 IU per day of either human menopausal gonadotrophin (HMG) or recombinant FSH (rFSH) for a fixed period of 7 days. The daily gonadotrophin dose was adjusted on the following day according to ovarian response. Patients blood was sampled for PP14 and hormone analysis on cycle days 21, S1, S8 and on the day of oocyte retrieval. Mean concentrations of PP14 on day 21 of the cycle were significantly lower in conception than in non-conception cycles, whereas progesterone and oestradiol were similar in conception and non-conception cycles. PP14 concentrations on the first day of stimulation and at oocyte retrieval were significantly higher in conception than in non-conception cycles, whereas concentrations after 8 days of stimulation were similar. Neither mode of GnRHa administration nor type of gonadotrophin significantly influenced PP14 concentrations throughout ovarian stimulation. Circulating PP14 is thus an important physiological signal of the fertility status of the individual in the cycle antecedent to and during ovarian stimulation. Measuring mid-luteal serum PP14 may offer a clinical test helping to decide if infertility treatment should be initiated in the subsequent cycle.

Metroplasty and Fetal Survival

During the period 1973–83, metroplasty for infertility was performed in 20 cases of symmetric uterine malformation. Apart from a vaginal septum in 2 cases, no other genital malformations were noted. A modified Jones & Jones technique was performed in 16 cases. 3 were unified a.m. Tompkins and 1 a.m. Strassman. No operative complications were noted. Prior to operation, 19 of the 20 women were pregnant, 46 times in all. Of these, 40 ended in spontaneous abortion, 5 in preterm birth, of which 2 infants survived, and 1 in birth at term. Postoperatively, 17 of the 20 women became pregnant, 22 times in all, and of these, 3 ended in spontaneous abortion and 19 with live infants born at term. The metroplasty changed the fetal survival rate from 6.5% prior to operation, to 86.4% after the operation. Pregnancy occurred 15 months, on average, after the operation. Only a few minor complications occurred during the pregnancies. Cesarean section was performed electively in 13 cases and acutely in 3 cases. A vaginal delivery occurred in the last 3 cases. There were only a few abnormal presentations and all the infants were born at term with a mean weight of 3400 g. Metroplasty seems to be an operation which clearly improves fetal survival rate in women with both symmetric uterine malformations and a history of habitual abortions and/or preterm births. Subsequent pregnancies are not associated with any increased risk of complications.