Single-dose GnRH agonist administration in the luteal phase of GnRH antagonist cycles: a prospective randomized study.

This study was designed to evaluate the effect of luteal-phase administration of single-dose gonadotrophin-releasing hormone (GnRH) agonist on pregnancy, implantation and live birth rates in patients who received GnRH antagonist for pituitary suppression. The study population consisted of 164 patients who underwent intracytoplasmic sperm injection (ICSI) after ovulation induction by gonadotrophins and GnRH antagonist for the prevention of a premature LH surge. For luteal-phase support, all the cases received intravaginal 600 mg micronized progesterone. In this prospective study, patients were randomly assigned to two groups. In one group, patients received an additional single dose of GnRH agonist (0.5 mg leuprolide acetate) subcutaneously on day 6 after ICSI, whereas the patients in the other group did not. Although the number of embryos transferred and the grade of the embryos were similar in the two groups, the patients in the luteal-phase agonist group had significantly higher rates of implantation and clinical pregnancy rates ( P < 0.05). When the two groups were compared, there were also statistically significant differences in multiple pregnancy and live birth rates ( P < 0.05). Administration of single-dose GnRH agonist as a luteal-phase support in ovarian stimulation-GnRH antagonist cycles in addition to standard luteal support seems to be effective in all cycle outcome parameters.

Pregnancies achieved by testicular sperm recovery in male hypogonadotrophic hypogonadism with persistent azoospermia.

Hypogonadotrophic hypogonadism is characterized by oligospermia or azoospermia and low testosterone, FSH and LH concentrations. In such cases, treatment with gonadotrophins is required to produce or increase spermatozoa in the ejaculate but few achieve normal spermatogenesis. After long periods of medical treatment, if the patients still have a low sperm count or azoospermia, assisted reproductive technologies in addition to hormone administration can be offered. Four cases of hypogonadotrophic hypogonadism with persistent azoospermia after at least 10 months of medical treatment are reported. In all four cases, spermatozoa retrieved by testicular sperm extraction and intracytoplasmic sperm injection (ICSI) were used to achieve fertilization. Excess spermatozoa were frozen in all cases. Six ICSI cycles using fresh testicular spermatozoa in four and thawed testicular spermatozoa in two were performed. Although there was no pregnancy in cycles where thawed spermatozoa were used, three clinical pregnancies were achieved in four cycles using fresh testicular spermatozoa. One of them ended with spontaneous abortion at 10 weeks of gestation and the two others resulted in the delivery of three normal offspring. If azoospermia persists after medical treatment, spermatozoa can be obtained surgically from testes and can be used successfully to achieve pregnancy in cases of hypogonadotrophic hypogonadism.

Combined approach as an effective method in the prevention of severe ovarian hyperstimulation syndrome.

The purpose of this study was to evaluate the effectiveness of combined approach on the prevention of severe ovarian hyperstimulation syndrome (OHSS) in high risk patients undergoing controlled ovarian hyperstimulation for IVF. The combined approach consisted of: (1) step-down administration of gonadotropins; (2) lowering the dose of human chorionic gonadotropin; (3) intravenous albumin infusion at the time of oocyte retrieval and (4) progesterone use for luteal support. Total of 87 high risk patients with a serum estradiol level >11,010 pmol/l or 3000 pg/ml on HCG day were managed by this combined approach and their results were compared with 274 low risk patients. In all high risk patients, the gonadotrophin dose were decreased starting as early as on day 4 of ovarian stimulation as necessary, ovulation was triggered by a decreased HCG dose of 5000-7000 IU according to the level of estradiol, intravenous infusion of 20% human albumin, 50-100ml were given just 1h before the oocyte retrieval and luteal support was provided either by 50mg progesterone in oil, IM or 600 mg micronized progesterone orally or vaginally until the day of beta-HCG determination. All patients were followed by serial ultrasonographic examinations and complete blood count analysis after embryo transfer to detect the early signs of OHSS and to allow early intervention. Age and duration of infertility were similar in both groups. Although the number of gonadotrophin ampoules used (22.7 +/- 4.7 versus 27.8+/-3.7; P<0.05) was significantly lower, estradiol levels (16,764 +/- 6936 pmol/l versus 8870 +/- 2456 pmol/l; P<0.05) and mean number of oocytes (18.3 +/- 5.9 versus 10.6+/-5.4; P<0.05) were significantly higher in study group. There was no significant difference between groups in terms of the mean number of transferred embryos (3.2 +/- 1.1 versus 3.4+/-1.1) and rate of pregnancies (50.5% versus 40.1%). There was only one moderate and no severe OHSS case in the high risk group, while five moderate and one severe OHSS cases developed in the control group consisting of low risk patients. In conclusion, intravenous albumin combined with low dose HCG, early step-down administration of gonadotropins and progesterone use for luteal support, so called combined approach, proved to be effective in the prevention of severe ovarian hyperstimulation syndrome in documented high risk patients.

Development of blastocyst-stage embryos after round spermatid injection in patients with complete spermiogenesis failure.

PURPOSE: Our purpose was to evaluate the progression of embryos derived from round spermatid injection to the blastocyst stage and compare the results with those obtained by the use of testicular or epididymal spermatozoa. METHODS: Thirty-eight patients with azoospermia enrolled in this study. In 29 patients with obstructive or nonobstructive azoospermia, spermatozoa were recovered from epididymis or testis. In the remaining nine cases with nonobstructive azoospermia, only round spermatids were found in seven, whereas in two of the patients, there were no elongated or round spermatids. Six of these cases underwent round spermatid injection. RESULTS: Twenty-one of 29 patients with injection of spermatozoa underwent embryo transfer on day 3, and 10 pregnancies (47.6%) were obtained. In eight cycles, embryos were further cultured for delayed transfer. In six cases undergoing round spermatid injection, no transfer was performed on day 3 and extended culture with delayed embryo transfer was applied. The mean number of fertilized oocytes and mean number of embryos on day 3 and also the fertilization rate and mean number of good-quality embryos on day 3, mainly grade 1 or 2, were statistically significantly higher in the spermatozoa group than the round spermatid injection group. Compared to the spermatozoa group, the number of arrested embryos was significantly higher and the number of blastocyst-stage embryos and number of good-quality blastocysts were significantly lower in the spermatid injection group. No blastocysts developed in two spermatid cycles and embryo transfer was not possible, and in the remaining four cycles, after at least one blastocyst transfer, no pregnancies were achieved. However, in eight cycles with extended culture in the spermatozoa group, embryo transfers were achieved in all and three pregnancies, for a pregnancy rate of 37.5%, were obtained after blastocyst transfer. CONCLUSIONS: Our preliminary results showed that round spermatid injection was associated with a significantly lower fertilization and embryo development rate and a significantly higher developmental arrest rate compared with the injection of spermatozoa. Extended culture and delayed embryo transfer did not improve the clinical outcome after round spermatid injection, and these results suggested a developmental failure in embryos preventing successful implantation after round spermatid injection.

Comparison of zona manipulated and zona intact blastocyst transfers: a prospective randomized trial.

PURPOSE: In this prospective randomized study the effects of enzymatic treatment of zona pellucida of blastocysts on implantation and pregnancy rates were evaluated in a group of patients who had more than five embryos on day 3. METHODS: Forty-six patients with a mean age of 29.8 +/- 4.5 years and mean duration of infertility of 6.72 +/- 0.63 years had blastocyst stage transfers, with a mean number of 2.9 +/- 0.1 embryos replaced per patient. Patients were randomly divided into two groups. The first group consisted of patients (n = 22) who had zona intact blastocyst stage transfers and the second group consisted of patients (n = 24) who had zona manipulated (enzymatic treatment) blastocyst stage transfers. Patient and cycle characteristics were similar in both groups. A commercial cell and serum-free sequential culture system was used for all embryos. RESULTS: Overall blastocyst formation rate was 50.3%. Transfer could be done in all patients. The positive beta-human chorionic gonadotropin rate in the zona intact group was 50% (11/22) and in the zona-manipulated group was 70.8% (17/24). Clinical pregnancy, ongoing pregnancy, and implantation rates in zona intact and manipulated groups were 45.5%, 27.3%, and 19%, and 62.5%, 45.8%, and 24% respectively. Although implantation and pregnancy rates in the zona-manipulated group were higher, there were no statistically significant differences in terms of these variables between two groups. No triplet pregnancy was obtained in either group, and the twin pregnancy rate was 20% (2/10) in the zona intact group and 13.3% (2/15) in the zona-manipulated group. CONCLUSIONS: With further improvements in the embryo culture systems it will become possible in the near future to achieve high implantation rates even with single blastocyst transfers. Enzymatic treatment of the zona pellucida seems that it does not alter the pregnancy and implantation rates, but further studies with larger group of patients are needed to clarify the real effect of this zona manipulation on pregnancy outcome.

Borderline form of empty follicle syndrome: is it really an entity?

We report two patients who were administered erroneously 1000 IU HCG instead of 10,000 IU for ovulation triggering in an assisted reproductive technology (ART) cycle. In one case no oocyte was retrieved from eight mature follicles after several washing attempts and retrieval day serum beta-HCG level was 21 mIU/ml. As there was no follicle in the other ovary we did not try a rescue protocol. In the other case two immature and one mature oocytes were retrieved from 15 mature follicles located in both ovaries. Retrieval day serum beta-HCG level was 12 mIU/ml. ICSI was performed in one mature and two in vitro maturated oocytes and the embryo transfer that was done 72 h after the retrieval yielded a healthy singleton pregnancy. Our experience shows that a borderline form of EFS may be an entity and it may be possible to see the formation of periovulatory events and even to obtain a pregnancy in an ART cycle where the ovulation was triggered by 1000 IU HCG.

Intracytoplasmic sperm injection is not associated with poor outcome in couples with normal semen parameters and previous idiopathic fertilization failure in conventional in vitro fertilization.

In this study, we compared the results of intracytoplasmic sperm injection (ICSI) in patients with normal semen parameters and a history of failed fertilization with conventional IVF (study group) and in patients with male factor infertility (control group). Patient and cycle characteristics were similar in both groups. The mean number of retrieved and metaphase II oocytes, fertilized oocytes, embryos developed, embryos transferred and the number of cycles with fertilization failure also did not differ between groups. Although differences were not statistically significant, pregnancy rate (56.3% vs. 31.5%), implantation rate (14.2% vs. 12%) and ongoing pregnancy rate (37.5% vs. 17.7%) per embryo transfer were higher in the study group than the ones in the control group. We concluded that previous idiopathic fertilization failure with conventional IVF is not associated with poor outcome in subsequent ICSI treatment.

Fertilization and development of a blastocyst-stage embryo after selective intracytoplasmic sperm injection of a mature oocyte from a binovular zona pellucida: a case report.

PURPOSE: Our purpose is to describe the development of a blastocyst-stage embryo after the selective fertilization of a mature oocyte from a binovular zona pellucida by intracytoplasmic sperm injection (ICSI). METHOD: A 34-year-old woman underwent intracytoplasmic sperm injection due to severe male-factor infertility. After oocyte retrieval, a binovular zona pellucida including one mature metaphase II oocyte and one immature oocyte at the germinal vesicle stage as well as nine metaphase II oocytes was injected with spermatozoa using a one-to-one approach. RESULTS: The injected mature oocyte of the binovular zona pellucida showed fertilization as evidence by the presence of two pronuclei and cleaved to a four-cell embryo on the second day, while the uninjected oocyte showed signs of degeneration. On the third day, this embryo further cleaved to six blastomeres with slight fragmentation and it reached the blastocyst stage on the sixth day. CONCLUSIONS: Selective fertilization of one oocyte from a binovular zona pellucida by ICSI may lead to the development of a morphologically normal blastocyst-stage embryo which can be used for embryo transfer in the presence of a limited number of embryos.

Emergency hysterectomy in modern obstetric practice. Changing clinical perspective in time.

OBJECTIVE: Emergency hysterectomy in obstetric practice is generally performed in the setting of life-threatening hemorrhage. A retrospective review based on hospital data of 67 patients undergoing emergency peripartum hysterectomy over 10 years was undertaken. METHODS: Comparison of two different time periods regarding the incidence and the indications of obstetric hysterectomies was made. RESULTS: The number of patients with hysterectomy in the first 5 years of the study period (1985-1989) was 43 and during the last 5 years (1990-1994) it was 24. The incidence of hysterectomy during 1985-1989 was 1 in 2495 deliveries and the most common indication for hysterectomy was uterine atony (42%) followed by placenta accreta (25.5%) and uterine rupture (21%). On the other hand, the incidence of hysterectomy during 1990-1994 was 1 in 4228 deliveries and the ranking of indications of hysterectomy was slightly different from group 1 as mostly placenta accreta (41.7%) followed by uterine atony (29.2%). The maternal mortality rate was 4.5% in this series. CONCLUSION: This study showed that over the last decade the incidence of emergency hysterectomy in obstetric practice has declined in our clinic due to availability of high standard obstetric care and more liberal use of cesarean section at risk deliveries, better controlled use of oxytocin and internal iliac artery ligation.

Impact of baseline cysts at the time of administration of gonadotropin-releasing hormone analog for in vitro fertilization.

OBJECTIVE: To assess the effects of cysts developed prior to the commencement of luteal phase gonadotropin-releasing-hormone-agonist (GnRH-a) in IVF cycles. DESIGN: Retrospective analysis. SETTING: In vitro fertilization program in a tertiary hospital infertility clinic. PATIENTS: Women stimulated for IVF-ET. All stimulations were down-regulated with GnRH-a commenced on day 21 in a long protocol before gonadotropin stimulation. MAIN OUTCOME MEASURE: Pregnancy rate. RESULTS: Twenty-five of 121 cycles had cysts >15 mm (20.6%); these were classified as baseline (nonfunctional) (n = 12) or corpus luteum (n = 13) cysts. They had significantly longer suppression periods and lower peak estradiol levels, and used more gonadotropins during stimulation. Cysts had no impact on the number of oocytes collected or fertilization and pregnancy rates. Patients with baseline cysts had a greater duration of suppression and required more gonadotropin than those with corpus luteum cysts or those without cysts. The cycle outcomes were similar between the groups, but baseline cyst formation is likely to increase the cost of IVF. CONCLUSION: These findings suggest that baseline cyst formation causes longer suppression duration and greater gonadotropin utilization, although an impact on pregnancy rates is unlikely.

Clomiphene citrate challenge test in the assessment of ovarian reserve before controlled ovarian hyperstimulation for intracytoplasmic sperm injection.

The objective of this study is to evaluate the performance of clomiphene citrate (CC) challenge test to predict diminished ovarian reserve before controlled ovarian hyperstimulation for intracytoplasmic sperm injection (ICSI). The 198 women who underwent the CC challenge test fulfilled the following criteria; over 35 years of age, removal of one ovary or previous ovarian surgery, the presence of ovarian endometrioma or previous poor response to ovarian hyperstimulation. Of the patients tested, 141 were found to have a normal CC challenge test while 57 had an abnormal result. The cancellation rate of the cycle with a poor response was significantly higher in women with an abnormal test (36.8%) than in those with a normal test (19.8%) (P < 0.05). The sensitivity of CC test for cycle cancellation was found to be 43% with a specificity of 76%, positive and negative predictive values of 37 and 80%, respectively. The estradiol values on hCG day, the number of retrieved oocytes and metaphase II oocytes and the rate of transfer cycles were significantly lower in females with an abnormal test. Women with normal test results had higher pregnancy rates per embryo transfer than those with abnormal test results (21.5 vs. 13.3%) and the predictive value of an abnormal test for failing to conceive was 93% (53/57) with a sensitivity of 31%, specificity of 84% and negative predictive value of 15.6%. Of 57 women with an abnormal test result, 25 (43.8%) were abnormal due only to an elevated day 10 or 11 value of FSH, which could not be detected using only basal FSH screening. In this group, the cancellation rate (48 vs. 19.8%, P < 0.01), the rate of transfer cycles (48 vs. 72.3%, P < 0.05) and the mean number of retrieved oocytes (4.9 +/- 2.5 vs. 6.4 +/- 3.1, P < 0.01) were all significantly different from normal test group. Although the rate of pregnancies per started cycle (8 vs. 15.6%) did not show a statistically significant difference, this is most probably due to the low number of patients. In conclusion, an abnormal CC challenge test is a good predictor of diminished ovarian reserve and it is better than a basal FSH concentration on day 3. It provides valuable information for both patients as to their chances of achieving a pregnancy and also for the medical team deciding on options for stimulation protocols.

A healthy birth after intracytoplasmic sperm injection by using immotile testicular spermatozoa in a case with totally immotile ejaculated spermatozoa before and after Percoll gradients.

Total asthenozoospermia is a severe problem, as only a micromanipulation technique can assist the couple, and even then fertilization and pregnancy rates are very low. The first healthy birth, achieved by using testicular immotile spermatozoa in a case with total asthenozoospermia before and after Percoll gradient preparation, is reported.

Endocrinological and clinical analysis of hyperprolactinemic patients with and without ultrasonically diagnosed polycystic ovarian changes.

In the present study we aimed to identify the relationship of hyperprolactinemia and polycystic ovarian changes. We retrospectively analyzed the endocrinological and clinical features of 79 hyperprolactinemic patients detected during a 3-year period ending in March 1995. Patients who had hypothyroidism, macroprolactinoma and drug-induced hyperprolactinemia were excluded from the study. Among 61 hyperprolactinemic patients, 41 (67.2%) had ultrasonographically diagnosed polycystic ovaries (PCO). Prolactin levels in the PCO and non-PCO groups were 32.8 +/- 5.8 and 36.7 +/- 5.1 ng/dl, respectively, which was a significant difference (p < 0.05). Hirsutism was associated with hyperprolactinemia in 55.7% of the patients and was found to be more frequent in the PCO (58.8%) than the non-PCO group (41.2%). The mean Ferriman Gallwey scores and both total and free testosterone levels were significantly higher in the PCO group in comparison to the non-PCO group. In addition, a significantly higher body mass index was detected in patients with PCO. We documented a frequent association between hyperprolactinemia and polycystic ovarian changes and suggested that hyperprolactinemia in PCO is most likely related to a pathologic-endocrinologic milieu.

Intravenous albumin prevents moderate-severe ovarian hyperstimulation in in-vitro fertilization patients: a prospective, randomized and controlled study.

OBJECTIVE: To assess the effectiveness of intravenous administration of albumin in prevention of ovarian hyperstimulation syndrome (OHSS) in patients of an in-vitro fertilization program. STUDY DESIGN: Prospective randomized study. Patients with hCG day E2 levels are 11010 pmol/l (3000 pg/ml) or more were recruited into two groups. Group A (n = 27) received 10 g 20%, 50 ml human albumin infusion before oocyte pick-up and no medication was administered in Group B (n = 28). RESULTS: Patients were similar in terms of cycle characteristics. No moderate-severe OHSS developed in Group A whereas one severe OHSS case and four moderate OHSS cases developed in Group B. Statistical analysis revealed a significant (P < 0.05) protection in albumin treated group. CONCLUSION: Human albumin proves effectiveness in prevention of moderate-severe OHSS.

Low dose ketoconazole is an effective and a relatively safe alternative in the treatment of hirsutism.

Efficacy, clinical and hormonal effect of ketoconazole in 400 mg/day dose was tested in a prospectively-designed study. Twenty four patients with hirsutism according to the Ferriman and Gallwey score (> 8) and elevated blood androgen levels were administered 400 mg/day ketoconazole for 6 months. Basal and posttherapy early follicular phase androgens and biochemical parameters were evaluated. In 22 patients significant improvement and in 2 slight improvement was seen in subjective complaints. No side-effects were observed in these patients other than 2 cases of pruritus (transient), 2 mild gastric upset and 1 mastodynia. All patients completed the study. Low dose ketoconazole seems to be effective in the treatment of hirsutism with relatively few side-effects but still should be reserved as an alternative choice due to the potential for deleterious hepatic effects.

Comparison of four different treatment regimes in hirsutism related to polycystic ovary syndrome.

Polycystic ovary syndrome is the most common endocrinological problem associated with hirsutism. The objective of this study was to compare four different treatment modalities for hirsutism related to this syndrome. Pelvic ultrasonography was performed on all patients who were referred to our Reproductive Endocrinology Outpatient Clinic because of complaints of hirsutism. After exclusion of hyperandrogenism caused by endocrine abnormalities other than polycystic ovary syndrome, 141 patients were included in the study. Patients were divided into four groups in regard to the drug chosen for treatment. Group 1 (n = 48) received low-dose combined oral contraceptive. Group 2 (n = 65) was treated with cyproterone acetate 100 mg daily for the first 10 days of a 21-day cycle with an oral contraceptive containing 2 mg cyproterone acetate, Group 3 (n = 12) with spironolactone (100-200 mg daily) and Group 4 (n = 16) with ketoconazole (400 mg daily). All patients were followed frequently with respect to side-effects, hirsutism scoring, and lipid and hormonal levels. All four drug regimens were effective in the treatment of hirsutism related to polycystic ovary syndrome, but the most effective seemed to be ketoconazole. The decrement level in hirsutism scoring was the largest in the ketoconazole group, followed by the cyproterone, oral contraceptive and spironolactone groups (34.6 +/- 2.2%, 20.1 +/- 2.7%, 18.1 +/- 2.7% and 12.8 +/- 3.7%, respectively, p < 0.05). Although high-density lipoprotein-cholesterol levels increased in all groups, this increment was smaller in Group 4 than in Groups 1 and 2 (5.1 +/- 2.8%, 34.1 +/- 5.5% and 29.1 +/- 4.9%, respectively, p < 0.05), but not statistically different from that in Group 3 (22.3 +/- 5.9%). The free testosterone levels decreased after treatment in all groups, but the decrement ratios did not differ significantly among groups, although the decrease in free testosterone levels with treatment seemed to be higher in the ketoconazole group than in Groups 1, 2 and 3 (57.0 +/- 2.5%, 22.7 +/- 10.2%, 26.7 +/- 6.5% and 9.5 +/- 19.9%, respectively). In conclusion, ketoconazole seems to be an excellent alternative to more-recognized therapies, but its effect on lipoprotein profile requires further study, because the hyperandrogenism, and the other problems related to hyperandrogenism besides hirsutism, should also be treated.