Successful Pregnancy and Delivery After Frozen-thawed Embryo Transfer Following the Third Discontinuation of Tyrosine Kinase Inhibitor in a Woman with Chronic Myeloid Leukemia.

Assisted reproductive technology is a viable option for pregnant women with chronic myeloid leukemia. We herein report the case of a patient who underwent successful fertility treatment with frozen embryo preservation at 36 years of age, followed by embryo transfer at 39 years of age, thus resulting in pregnancy and delivery after a third discontinuation of tyrosine kinase inhibitors (TKI). Despite the difficulty of long-term TKI withdrawal, the patient's strong desire for a baby led to a successful pregnancy and delivery with no apparent deformities or abnormalities. Thus, our case highlights the importance of collaboration between reproductive medicine physicians and hematologists.

Mitochondrial DNA mutations can influence the post-implantation development of human mosaic embryos.

Introduction: Several healthy euploid births have been reported following the transfer of mosaic embryos, including both euploid and aneuploid blastomeres. This has been attributed to a reduced number of aneuploid cells, as previously reported in mice, but remains poorly explored in humans. We hypothesized that mitochondrial function, one of the most critical factors for embryonic development, can influence human post-implantation embryonic development, including a decrease of aneuploid cells in mosaic embryos. Methods: To clarify the role of mitochondrial function, we biopsied multiple parts of each human embryo and observed the remaining embryos under in vitro culture as a model of post-implantation development (n = 27 embryos). Karyotyping, whole mitochondrial DNA (mtDNA) sequencing, and mtDNA copy number assays were performed on all pre- and post-culture samples. Results: The ratio of euploid embryos was significantly enhanced during in vitro culture, whereas the ratio of mosaic embryos was significantly reduced. Furthermore, post-culture euploid and culturable embryos had significantly few mtDNA mutations, although mtDNA copy numbers did not differ. Discussion: Our results indicate that aneuploid cells decrease in human embryos post-implantation, and mtDNA mutations might induce low mitochondrial function and influence the development of post-implantation embryos with not only aneuploidy but also euploidy. Analyzing the whole mtDNA mutation number may be a novel method for selecting a better mosaic embryo for transfer.

Add-on effects of oral tocopherol supplementation to surgical varicocelectomy on the outcome of assisted reproductive technology: a single-center pilot study report.

Introduction: Varicocelectomy is well known to improve the pregnancy outcome of patients with clinical varicoceles in assisted reproductive technologies as well as spontaneous conception. Therefore, this study aimed to evaluate the additional effects of oral antioxidant therapy after varicocelectomy on the pregnancy outcome in the assisted reproductive technology setting. Methods: This study was a retrospective cohort study. The subjects were couples among whom the male partner had undergone varicocelectomy and was scheduled for subsequent assisted reproductive technology. Pregnancy outcomes were followed retrospectively in 62 couples with male partners who received tocopherol (antioxidant group) and 37 couples who did not (control group). The tocopherol and control groups were assigned dependent on the decision of the physician in charge and the patient's request. The clinical pregnancy rates per couple and embryo transfer, time to pregnancy, and the number of cycles during transfer to pregnancy were evaluated. Results: No significant differences were observed in the pregnancy rate per couple (antioxidant group 70.9% vs. control group 64.9%, P = 0.55) and per embryo transfer (50.4% vs. 39.6%, P = 0.22). Regarding the time to event analyzed by adjusted restricted mean survival time, the mean time to pregnancy was significantly shorter in the antioxidant (tocopherol) group (14.2 vs. 17.4 months, P = 0.025). No significant difference was observed in the embryo transfer cycle to pregnancy (mean embryo transfer cycles: 2.6 vs. 3.0, P = 0.238). Conclusions: Additional oral tocopherol nicotinate as antioxidant therapy after varicocelectomy was shown to shorten the time to pregnancy. It is recommended that add-on effects be tested in more well-designed randomized controlled trials to examine whether it improves assisted reproductive outcomes.

Fertility preservation immediately after therapeutic abortion results in multiple normal follicular growth with the absence of mature oocytes due to early luteinization: a case report and literature review.

Cancer therapy has priority over fertility preservation. The time available for fertility preservation in patients with cancer is often very limited and depends on the condition of the underlying disease. This case report presents the results of two rounds of controlled ovarian stimulations (COSs) performed after an induced abortion. The patient had mixed phenotype acute leukemia diagnosed during early pregnancy and underwent a surgical abortion, followed by ovarian stimulation using urinary follicle-stimulating hormone (uFSH) and gonadotropin-releasing hormone (GnRH) agonists. Oocyte retrieval was subsequently performed for oocyte cryopreservation. Despite good hormonal and ultrasonic follicular growth, no oocytes were obtained. During a second COS performed at a low human chorionic gonadotropin (hCG) level (less than 100 IU/L), several mature oocytes were obtained, suggesting that higher hCG levels during COS induce the absence of mature oocytes during normal follicular growth. It is recommended to start COS post-abortion after confirming a low hCG level while considering the timing of cancer treatment.

Early and late paternal effects of reactive oxygen species in semen on embryo development after intracytoplasmic sperm injection.

Although reactive oxygen species in semen are associated with unfavorable results with respect to assisted reproductive technology, their effects based on the detailed stages of embryo development are unclear. We investigated the relationship between reactive oxygen species in semen and the oocyte fertilization rate, cleavage rate, and blastulation rate of intracytoplasmic sperm injections. This retrospective study enrolled 77 couples who underwent intracytoplasmic sperm injection and analyzed 887 eggs from 141 cycles of intracytoplasmic sperm injection. The reactive oxygen species level in semen was compared between the fertilized and nonfertilized groups, between the good-cleavage-embryo and non-developed-embryo groups, and between the good-quality-blastocyst and poor-quality-blastocyst groups. The cut-off level of reactive oxygen species was calculated to predict good-cleavage-embryo and good-quality-blastocyst development. The fertilization rate was 65.4%, and the mean reactive oxygen species levels were not significantly different between the fertilized and nonfertilized groups. The reactive oxygen species level was significantly higher in the non-developed-embryo group than in the good-cleavage-embryo group (P = 0.0026) and was significantly lower in the good-quality-blastocyst group than in the poor-quality-embryo group (P = 0.015). Cleavage embryos and blastocysts were divided into high- and low-reactive-oxygen-species groups using a cut-off value of 6601 and 4926 relative light units, as calculated from the receiver operating characteristic curve. The rates of good-cleavage embryos and good-quality blastocysts were lower in the high-reactive-oxygen-species group than in the low-reactive-oxygen-species group, which were both statistically significant. To conclude, reactive oxygen species in semen is considered to have an adverse effect on both the early and late stages of embryo development in intracytoplasmic sperm injection.Abbreviations: GnRH, gonadotropin-releasing hormone; ICSI, intracytoplasmic sperm injection; IVF, in vitro fertilization; LPO, lipid peroxidation; NADPH, nicotinamide adenine dinucleotide phosphate; RLU, relative light units; ROC, receiver operating characteristic; ROS, reactive oxygen species.

A case of empty follicle syndrome who conceived after aspiration of an endometrial cyst.

Empty follicle syndrome (EFS) has been defined as a condition where no oocytes can be retrieved for in vitro fertilization (IVF) even though ultrasound findings and estradiol (E2) levels suggest the presence of potential follicles. The EFS is a rare condition with an incidence of 0.5-7 % of women undergoing IVF treatments. Although there are many hypotheses as to the cause of EFS, including advanced ovarian age, drug-related problems, and dysfunctional folliculogenesis, its cause remains unknown. A 37-year-old woman with endometriosis and a 5-year history of primary infertility underwent IVF treatment for 4 cycles. No oocytes were retrieved in 2 cycles and no fertilized eggs were obtained in the other 2 cycles. We assumed that endometriosis adversely affected folliculogenesis and fertilization. Aspiration of an endometrial cyst in the right ovary and subsequent administration of oral contraceptives resulted in successful folliculogenesis and fertilization. Thereafter, she conceived and delivered a 2,662 g female infant at 38 weeks of gestation. Here, we report a case of EFS who conceived in the 5th IVF cycle after aspiration of an endometrial cyst. We assumed that endometriosis might have been involved in the dysfunction of folliculogenesis and EFS.

[Y-autosome translocation associated with male infertility: a case report].

A 40-year-old man was referred to our hospital with a 12-year history of infertility. He was a well developed male weighing 78 kg with a height of 171 cm. Physical examinations revealed male habitus with normal adult pubic and axillary hair. The penis, epididymides, spermatic cords and prostate were normal. The right testis was about 15 ml in volume and left ne was approximately 12 ml, respectively. Repeated semen analyses showed azoospermia except for only one time when 4 immotile sperm were detected. The plasma levels of lactate hydrogenase, follicle stimulating hormone prolactin and testosterone were within normal limits. Chromosome analysis of peripheral lymphocytes revealed a balanced reciprocal translocation between the short arm of chromosome 12 and the long arm of the Y chromosome (46, X, t (Y ; 12) (q12 ; p13.3)). We performed microdissection testicular sperm extraction and retrieved 11 spermatozoa (10 progressive motile). Seminiferous epithelium showed maturation arrest at the stage of spermatid. Mean Johnsen's score count was 6. The etiology and clinical features of this rare disease were briefly discussed.

Retrospective analysis of laparoscopic salpingostomy and conservative expectant management of tubal ectopic pregnancy.

PURPOSE: To identify predictive factors for successful expectant management of ectopic pregnancy and to evaluate the prognosis for fertility after expectant management and laparoscopic salpingostomy. METHODS: Forty-six cases of expectant management and eighty cases of laparoscopic salpingostomy for tubal ectopic pregnancy were retrospectively analyzed. Subjects were classified in three groups: those who underwent laparoscopic salpingostomy, those treated by expectant management only, and those treated by expectant management but requiring additional treatment. RESULTS: The rates of tubal patency, intrauterine pregnancy and repeated ectopic pregnancy in the laparoscopic salpingostomy group were 75, 40, and 16%. The rates in the expectant management group were not significantly different: 72, 42 and 15%. Finally, the rates in the extra treatment group were 75, 39 and 15%. Success rate of expectant management was 54%. In 93% of cases expectant management was successfully completed when the initial levels of urinal hCG were less than 3000 mIU/ml and the levels of hCG 48 h later were less than 80% of the initial levels. However, expectant management alone was insufficient and required extra treatment in 90% of cases when the initial levels of hCG were 3000 mIU/ml and above or when the levels of hCG level 48 h later was 80% of initial levels and above. CONCLUSIONS: Expectant management in combination with salpingostomy is not only minimally invasive but also a useful way to preserve fertility. Initial urine hCG levels and their variation over time can help predict whether expectant management will succeed.

Hypoadiponectinemia in lean lactating women: Prolactin inhibits adiponectin secretion from human adipocytes.

Adiponectin is an adipocyte-derived hormone involved in glucose, lipid and energy metabolism. A low plasma adiponectin concentration is associated with insulin resistance, obesity and atherosclerosis. In women, energy homeostasis is remarkably changed during gestation and lactation in order to supply sufficient nutrition for a fetus or newborn. In this study we aimed to elucidate the physiological impact of gestation and lactation on the plasma adiponectin levels and the influence of reproduction-related hormones on adiponectin secretion. We studied the longitudinal changes in plasma adiponectin concentration during pregnancy (1st, 2nd and 3rd trimester) and lactation (3 days and 1 month after the delivery) in lean healthy women (n = 22). The plasma adiponectin level declined slightly as the pregnancy advanced and reached its lowest level during lactation (12.25 +/- 0.182 microg/ml at early pregnancy vs. 6.88 +/- 0.375 microg/ml at 3 days postpartum, p < 0.001). In order to investigate the role of the lactogenic hormone prolactin in the decrease of plasma adiponectin levels during lactation, we further performed in vitro experiments using human primary cultured adipocytes. Western blotting of the adipocyte lysate and ELISA of the culture medium revealed that exogenous prolactin inhibited both production and secretion of adiponectin in a dose-dependent manner. Our results thus suggests that prolactin affects the regulation of maternal metabolism through suppression of adiponectin.

GnRH antagonist-induced down-regulation of the mRNA expression of pituitary receptors: comparisons with GnRH agonist effects.

In order to compare the mechanism for the down regulation of the mRNA expression of pituitary receptors induced by GnRH antagonist (GnRHant) to that by GnRH agonist (GnRHa), we examined the effects of GnRHant (Cetrorelix, 333 mug/kg/day), GnRHa (leuprolide depot, 333 microg/kg), and GnRHant combined with GnRHa on LH response to exogenous GnRH, pituitary LH content, LH beta subunit mRNA, and GnRH receptor (GnRH-R) mRNA levels at 2, 5, 24, 72 hours, and 7 days after the treatment in ovariectomized rats. GnRHant significantly decreased serum LH, the LH response of the pituitary to exogenous GnRH, and the pituitary LH content compared to the control treatment, though GnRHa significantly increased serum LH. GnRHant with GnRHa significantly diminished the GnRHa-induced flare-up phenomenon. GnRHant significantly decreased LH beta mRNA and GnRH-R mRNA levels, but the magnitude of the decrease in these mRNA levels by GnRHant was significantly less than those by GnRHa until 72 hours following treatment. Prolonged treatment of GnRHant caused a marked inhibition of LH beta mRNA and GnRH-R mRNA expression, similar to that caused by GnRHa. Combination treatment with GnRHa and GnRHant was demonstrated to decrease LH beta mRNA and GnRH-R mRNA levels as much as GnRHa alone and GnRHant alone over 7 days of the treatment. The present study showed differences between GnRHant and GnRHa treatment in the reduction of GnRH-R mRNA levels up to 72 hours after the treatment, and indicated that the suppression of GnRH-R mRNA by GnRHant was the maximal by GnRHa 7 days after the treatment because more profound suppression was not observed upon additional treatment with GnRHa. The findings in the present study support the hypothesis that the mechanism by which GnRHant leads to down-regulation of the mRNA expression of pituitary receptors is similar to that of GnRHa.

Role of corticotropin-releasing hormone in ovarian steroidogenesis.

The physiologic role of corticotropin-releasing hormone (CRH) was examined in the ovary. We investigated the effects of CRH on steroidogenesis in rat and human granulosa cells in vitro as well as the direct effects of CRH on the ovary in vivo. We further examined the gene expression of CRH in human granulosa cells. CRH significantly inhibited the production of estradiol (E2) and progesterone (P4) in rat and human granulosa cells in vitro. These inhibitory effects were completely abolished by alpha-helical CRH, a CRH receptor antagonist. Forskolin-induced increase in E2 and P4 production was attenuated by CRH. On the other hand, CRH significantly increased serum concentrations of E2 and corticosterone in vivo in hypophysectomized rats, but this increase was completely blocked by adrenalectomy. It is probable that these effects did not result from a direct action on the ovary but were an indirect effect via the adrenal gland. Finally, by reverse transcriptase polymerase chain reaction we demonstrated that CRH mRNA was expressed in human granulosa cells. Our findings indicate that CRH exerts inhibitory effects on steroidogenesis in rat and human granulosa cells, acting through the CRH receptor. These effects are attributed to cellular events downstream of cyclic adenosine monophosphate generation. CRH seems to modulate steroidogenesis via autocrine or paracrine actions in the ovary.

A modified hMG-GnRH method for the induction of ovulation in infertile women with severe hypogonadotropic amenorrhea.

The objective of this study was to compare, in infertile women suffering from severe hypogonadotropic amenorrhea, the therapeutic utility and the incidence of complications arising from fertility treatment by the conventional human menopausal gonadotropin/human chorionic gonadotropin (hMG-hCG) method, the hMG step-down method, the sequential hMG/gonadotropin-releasing hormone (GnRH) method and a new, modified hMG-GnRH method that has been developed by us. In the step-down method, the daily dose of hMG was decreased from 150 IU to 75 IU when the follicle diameter reached 11-13 mm. In the sequential hMG-GnRH, hMG injection was switched to pulsatile GnRH administration (20 microg/120 min SC), when the follicle diameter reached 11-13 mm. In our new modified hMG-GnRH, pulsatile GnRH was injected together with hMG. Daily hMG was stopped and the GnRH dosage was changed from 10 microg to 20 microg when the follicle diameter reached 11-13 mm. Initially, the three established methods were applied randomly to treat 34 cycles in 20 women; and subsequently, five patients who failed to conceive following treatment by sequential hMG-GnRH were then treated by the modified hMG-GnRH method. More than eight growing follicles and multiple pregnancies were observed during treatment by the conventional method. The incidence of ovarian hyperstimulation syndrome (OHSS) was 25.7% with the conventional method, 20.0% with the step-down method and 0% with the sequential hMG-GnRH method; however, the rate of ovulation was only 50% with the sequential hMG-GnRH method. By contrast, with the modified hMG-GnRH method, less than three growing follicles occurred in 81.8% of patients, there was a 100% rate of ovulation, and neither OHSS nor multiple pregnancies were observed. Moreover, the modified hMG-GnRH method induced pregnancy in 3 out of 5 patients. These data indicate that this new method is favorable for the treatment of severe hypogonadotropic amenorrhea.