We report a rare case of delayed implantation of frozen-thawed embryo transfer in a hormone-controlled cycle due to delayed window of implantation (WOI). Synchronizing embryo growth with the endometrial hormonal environment is important... more
We report a rare case of delayed implantation of frozen-thawed embryo transfer in a hormone-controlled cycle due to delayed window of implantation (WOI). Synchronizing embryo growth with the endometrial hormonal environment is important for successful implantation. Initially, our patient underwent multiple unsuccessful endometrium-matched blastocyst transfers after five days of progesterone treatment. We found that day 3 embryo and two-day delayed blastocyst transfers were more successful than the normal blastocyst transfer. Finally she underwent two successful single embryo implants that resulted in pregnancies. We suggest that a delay in the WOI may have been the cause for the recurrent implantation failure.
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Problem: To evaluate the effect of hypoxia on interleukin (IL)‐8 expression in human ovarian follicles.Method of study: Follicular fluid (FF) from each follicle was separately collected from women undergoing in vitro fertilization and... more
Problem: To evaluate the effect of hypoxia on interleukin (IL)‐8 expression in human ovarian follicles.Method of study: Follicular fluid (FF) from each follicle was separately collected from women undergoing in vitro fertilization and embryo transfer. Concentrations of oxygen, progesterone, estradiol, IL‐1α/β, IL‐8, and tumor necrosis factor (TNF)‐α in FF were measured. Isolated granulosa‐lutein cells (GLC) from obtained FF were cultured under normoxic or hypoxic conditions, and concentrations of IL‐8 in culture media were measured.Results: Simple regression analysis demonstrated a significant negative correlation between the concentrations of IL‐8 and oxygen in FF (r = 0.50, P < 0.0001). However, none of the concentrations of progesterone, estradiol, IL‐1β, and TNF‐α in FF showed a significant correlation with IL‐8 concentrations. Hypoxia stimulated the secretion of IL‐8 by cultured GLC over twofolds compared with a normoxic control (P < 0.05).Conclusions: These findings suggest that IL‐8, like other angiogenic factors, is upregulated under hypoxic condition, which argues that hypoxia in the ovarian follicles comes into play in ovarian functions by inducing a range of proangiogenic and chemoattractive substances.
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Problem: To assess whether interferon‐γ‐induced protein‐10 (IP‐10), a chemokine that has antiangiogenic activities, may be involved in the pathogenesis of endometriosis.Method of Study: A total of 120 patients undergoing laparoscopy for... more
Problem: To assess whether interferon‐γ‐induced protein‐10 (IP‐10), a chemokine that has antiangiogenic activities, may be involved in the pathogenesis of endometriosis.Method of Study: A total of 120 patients undergoing laparoscopy for pain and/or infertility were recruited, and peritoneal fluid (PF) and bone marrow derived cells in PF were collected. Concentrations of IP‐10 in PF were measured with a specific enzyme‐linked immunosorbent assay. Expression of IP‐10 and IP‐10 receptor, CXCR3, in bone marrow derived cells in PF, peritoneum and endometriotic cells was analyzed by reverse transcription‐polymerase chain reaction.Results: All of the PF samples examined contained detectable concentrations of IP‐10. In women with advanced stages of endometriosis, IP‐10 concentrations in PF were significantly lower than those of women in early stages (P = 0.02). The IP‐10 concentrations in women with advanced endometriosis also appeared to be lower than those without endometriosis although the difference was statistically marginal (P = 0.06). The expression of both IP‐10 and CXCR3 was clearly detected in the bone marrow derived cells in PF, peritoneum and endometriotic stromal cells.Conclusions: Decreased concentrations of IP‐10 in PF from women with advanced stages of endometriosis may imply that the peritoneal environment of these women is permissive to the development of the disease by enhancing angiogenesis and/or modulating inflammatory/immunological responses.
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Research Interests: Information Systems, Genetics, Genomics, Biology, Humans, and 15 moreCorpus Callosum, Caudate Nucleus, Female, Male, Alternative splicing, Human Brain, Fluorescent in situ hybridization, Amino Acid Profile, Alternative Splicing, Amino Acid Sequence, Immunoglobulin, Gene Expression Regulation, Chromosome Banding, Contactins, and Expression pattern
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Research Interests: Biology, Medicine, Pregnancy, Humans, bisphenol A, and 15 moreFemale, Blood sampling, Amniotic Fluid, Phenols, Human reproduction, Foetus, Postnatal development, Fetus, Gestation, Embryos, Body Fluids, Follicular Fluid, Enzyme Linked Immunosorbent Assay, Human Exposure, and Medical and Health Sciences
Research Interests: Pergamon, Growth, Pregnancy, Low Dose, Reproductive toxicology, and 15 morebisphenol A, Mice, Female, Animals, Male, Blastocyst, Phenols, Embryonic Development, Public health systems and services research, Postnatal development, Body Weight, Embryos, Prenatal Exposure, Paediatrics and reproductive medicine, and Pharmacology and pharmaceutical sciences
Research Interests: Endocrinology, Chemistry, Medicine, Internal Medicine, Testosterone, and 15 moreLiver, bisphenol A, Endocrine disruptors, Female, Animals, Endocrine, Clinical Sciences, Phenols, Rats, Sex Factors, Endocrine Disruptors, Estradiol, Ovariectomy, reverse transcriptase polymerase chain reaction, and glucuronosyltransferase
The epigenetic status of the genome changes dynamically from fertilization to implantation. In addition, the physiological environment during the process of gametogenesis, including parental age, may affect the epigenome of the embryo... more
The epigenetic status of the genome changes dynamically from fertilization to implantation. In addition, the physiological environment during the process of gametogenesis, including parental age, may affect the epigenome of the embryo after fertilization. It is important to clarify the influence of parental age on gene expression in the embryo in terms of transgenerational epigenetics to improve the techniques currently used in assisted reproductive medicine. Here, we performed single-embryo RNA-seq analysis on human blastocysts fertilized by intracytoplasmic sperm injection, including from relatively elderly mothers, to elucidate the effects of parental age on the embryonic gene expression profile. We identified a number of genes in which the expression levels were decreased with increasing maternal age. Among these genes, several are considered to be important for meiotic chromosomal segregation, such as PTTG1, AURKC, SMC1B and MEIKIN. Furthermore, the expression levels of certain...
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Enzyme activities were determined quantitatively in individual rat oocytes to study their energy metabolism during maturation. Low hexokinase activity and high activities of lactate dehydrogenase and enzymes in the phosphate pathway,... more
Enzyme activities were determined quantitatively in individual rat oocytes to study their energy metabolism during maturation. Low hexokinase activity and high activities of lactate dehydrogenase and enzymes in the phosphate pathway, i.e., glucose 6-P and 6-P gluconate dehydrogenases, were characteristic of immature oocytes. Hexokinase may be a rate-limiting enzyme that enables oocytes to use glucose as an energy source. During maturation, the activities of hexokinase, phosphofructokinase, and malate dehydrogenase increased significantly, suggesting that the glycolytic pathway, as well as the tricarboxylic acid cycle, developed as the first meiotic division proceeded. In contrast, the activities of glucose 6-P and 6-P gluconate dehydrogenases decreased in maturing oocytes. The observation that the enzyme pattern in mature oocytes resembles more closely that in somatic cells appears to be significant, especially in light of previous studies showing this developmental trend in preimplantation embryos.
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Objective: To examine how preexisting tubal adhesions and endometriosis affect pregnancy outcome after laparoscopic treatment in infertile women with no apparent causes of infertility other than tubal factors. Study design: Pregnancy... more
Objective: To examine how preexisting tubal adhesions and endometriosis affect pregnancy outcome after laparoscopic treatment in infertile women with no apparent causes of infertility other than tubal factors. Study design: Pregnancy outcomes in 186 infertile women for a follow-up period of 18 months after laparoscopy were analyzed. Laparoscopic manipulations consisted of adhesiolysis of tubes and removal of endometriotic lesions. Results: The patients were classified into three groups, those with no tubal adhesions (group A, n = 83), unilateral tubal adhesions (group B, n = 46) and bilateral tubal adhesions with at least one tube patent (group C, n = 57). The cumulative pregnancy rate in group C (13.2%) was lower than in groups A (41.8%) and B (45.7%) 18 months after laparoscopy. The average time to conception in group A (6.7 +/- 0.8 months) tended to be shorter than that in group B (10.6 +/- 1.2 months). In group A, pregnancy rates were essentially the same between minimal/mild endometriosis and moderate/severe endometriosis. Regarding group B, women with minimal/mild endometriosis exhibited significantly higher pregnancy rates than those with moderate/severe endometriosis, while pregnancy rates in women without endometriosis fell in between. Conclusion: Pregnancy rates after laparoscopic treatment are different in relation to tubal status and the presence of endometriosis.
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Research Interests: Hypoxia, Cell Culture, In Vitro, Humans, Anoxia, and 15 morecyclic AMP, Female, Hormones, In Vitro Fertilization, Embryo Transfer, Clinical Sciences, Adult, Western blot, Biological activity, Granulosa Cells, Follicular Fluid, Corpus Luteum, Human Chorionic Gonadotropin, reverse transcriptase polymerase chain reaction, and Paediatrics and reproductive medicine
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Research Interests: Female, Ovulation, Animals, Ovarian Follicle, Rats, and 3 moreProstaglandins, Oocytes, and Indomethacin
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Secretion of growth hormone (GH) is known to be suppressed in women with polycystic ovary syndrome (PCOS). The suppression may be implicated in the pathogenesis of PCOS. To investigate the cause of suppressive GH secretion in PCOS. In... more
Secretion of growth hormone (GH) is known to be suppressed in women with polycystic ovary syndrome (PCOS). The suppression may be implicated in the pathogenesis of PCOS. To investigate the cause of suppressive GH secretion in PCOS. In order to eliminate the influence of obesity on the variables, all subjects were non-obese. Standard oral glucose tolerance tests (OGTT) were performed in 13 normal women and 15 patients with PCOS. The serum GH level decreased progressively during the OGTT, and the mean area under the curve (AUC) for the GH response was significantly smaller in the PCOS group than in the normal group. A reduction in the level of serum free fatty acids (FFAs) was observed during OGTT, but only the fasting level of FFAs was significantly higher in the PCOS group than in the normal group. The mean AUCs for glucose, insulin and FFA responses in the PCOS group were significantly greater than those in the normal group. There was a significant negative correlation only between AUC(GH) and testosterone (r = -0.4557, p = 0.012). Our findings suggest that the cause of susceptibility for GH secretion to be suppressed after glucose loading in non-obese PCOS patients may be hyperandrogenemia.
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Research Interests: Humans, Prolactin, bisphenol A, Female, Male, and 15 moreGender Difference, Androgens, Body Mass Index, Polycystic Ovary Syndrome, Phenols, Adult, Luteinizing Hormone, Enzyme Linked Immunosorbent Assay, Estradiol, Follicle stimulating hormone, Biochemistry and cell biology, Androstenedione, Human Exposure, Medical biochemistry and metabolomics, and free testosterone
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We previously identified a human estrogen-responsive gene, EBAG9 (ER-binding fragment-associated antigen9) (Watanabe, T. et al., Mol. Cell. Biol. 18, 442–449, 1998). It was later reported as RCAS1 (receptor-binding cancer antigen... more
We previously identified a human estrogen-responsive gene, EBAG9 (ER-binding fragment-associated antigen9) (Watanabe, T. et al., Mol. Cell. Biol. 18, 442–449, 1998). It was later reported as RCAS1 (receptor-binding cancer antigen expressed on SiSo cells) that induced apoptosis and suppressed the growth of several cells such as activated T cells (Nakashima, M. et al., Nat. Med. 5, 938–942, 1999). Here, we
Research Interests: Biological Chemistry, Cell Division, Biological Sciences, Endotoxin, Antibodies, and 15 moreFemale, Animals, Biochemical, Gene, Chromatin structure, CHEMICAL SCIENCES, Cattle, Estrogens, Amino Acid Sequence, Base Sequence, DNA probes, Biochemistry and cell biology, Biology Reproduction, Fallopian tubes, and Cricetinae
Our objective was to study the direct action of luteinizing hormone-releasing hormone (LHRH) agonist buserelin and LHRH antagonist Cetrorelix (SB-75) on cell proliferation and differentiation in the rat ovarian follicle. Preovulatory... more
Our objective was to study the direct action of luteinizing hormone-releasing hormone (LHRH) agonist buserelin and LHRH antagonist Cetrorelix (SB-75) on cell proliferation and differentiation in the rat ovarian follicle. Preovulatory follicles were isolated from PMSG-primed immature rats and incubated in the presence or absence of hCG (10 IU/ml), buserelin (10(-9)-10(-6) M) or Cetrorelix (10(-9)-10(-6) M) for 12 h in vitro. Buserelin induced meiotic maturation of the follicle-enclosed oocytes dose-dependently. The percentage of oocytes with germinal vesicle breakdown at 10(-6) M buserelin (73.3%) did not differ from that of hCG-treated control (73.3%). Buserelin also significantly stimulated prostaglandin E2 and progesterone production by follicles, but not estradiol production. Granulosa cells were obtained from the preovulatory follicles and cultured for 5 days. Epidermal growth factor (EGF) stimulated granulosa cell growth at concentrations of 1, 10 and 100 ng/ml. In contrast, bo...
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Recently, considerable attention has been focused on certain environmental contaminants, endocrine disruptors, of industrial origin that may mimic the action of estrogen. Oral contraceptives containing ethynylestradiol, a synthetic... more
Recently, considerable attention has been focused on certain environmental contaminants, endocrine disruptors, of industrial origin that may mimic the action of estrogen. Oral contraceptives containing ethynylestradiol, a synthetic estrogen, have been suspected to have adverse environmental effects since prenatal exposure to diethylstilbestrol, another synthetic estrogen, was reported to be associated with clear cell adenocarcinoma of the vagina in female offspring. In terms of magnitude and extent, such exposures to synthetic estrogens are now considered virtually insignificant compared with the secretion and excretion of natural estrogens from humans. However, as is the case with all other chemicals, continuous and rational risk assessment and risk management of these synthetic estrogens must be made.
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The sex-determining region on the Y chromosome (SRY) encodes a gene that has many of the properties expected of the testis-determining factor. The XY pure gonadal dysgenesis is characterized by streak gonads in phenotypic females who lack... more
The sex-determining region on the Y chromosome (SRY) encodes a gene that has many of the properties expected of the testis-determining factor. The XY pure gonadal dysgenesis is characterized by streak gonads in phenotypic females who lack the somatic abnormalities and short stature associated with Turner's syndrome. Abnormalities within the SRY have been described in these patients. However, we have experienced several patients with short stature whose SRY are apparently normal. The DNA sequencing of the SRY gene showed a 100% nucleotide sequence identity with the reported cloned sequence. Sex reversal in two of the present cases may be due to mutation at a locus other than SRY in the sex determining pathway, a gene potentially involved in the determination of human constitution. The risk of developing malignancy in the dysgenetic gonads has been reported to be 25%, dictating early prophylactic removal of the streaks. Laparoscopic surgery is recommended because of the amount of ...
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We studied the methylation status of the CpG island of the FMR-1 (fragile X syndrome) gene to recognize the possibility of its prenatal diagnosis with early pregnant subjects. Southern hybridization using EcoRI/BssHII restriction enzymes... more
We studied the methylation status of the CpG island of the FMR-1 (fragile X syndrome) gene to recognize the possibility of its prenatal diagnosis with early pregnant subjects. Southern hybridization using EcoRI/BssHII restriction enzymes double digestion was performed in the brain and chorionic villi of 8th week embryos, and the placenta and cord blood of newborns. No methylation of the FMR-1 gene occurred in both of the tissues examined in males, while 50% of the cells in females were methylated in both the brain and the cord blood, indicating that methylation occurs with inactivation of the X-chromosome in accordance with the literature. However, there was no methylation in either the chorionic villi or placenta in female as well as in males. Some extra-embryonic tissues such as the chorionic villi and the placenta escape X-chromosome FMR-1 gene inactivation and it can be the exception in the lyonization. To assess the methylation status in prenatal diagnosis, precautions are need...
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A microassay method sensitive enough to analyze the enzyme activities in one oocyte was developed using enzymatic cycling for amplifying the reaction product to 10,000 fold. An oil-well technique was applied in the assay for achieving the... more
A microassay method sensitive enough to analyze the enzyme activities in one oocyte was developed using enzymatic cycling for amplifying the reaction product to 10,000 fold. An oil-well technique was applied in the assay for achieving the reaction in the medium as small as 1.0 to 5.0 microliter. Immature Wistar rats were superovulated by PMS-hCG administration. Oocytes were collected by the puncture of the follicle and the flushing of the tube. They were freeze-dried after washing to remove cumulus cells. The dry weight was about 50ng on a quartz fiber fishpole balance. The activity of hexokinase was 1.75 +/- 0.14 picomol/oocyte/hr corresponding to one-tenth of the ovarian homogenate as control, indicating low capacity of glucose utilization in the oocyte. The activities of G6PD, LDH, and MDH were 8.41 +/- 0.34, 35.7 +/- 2.89. 11.1 +/- 2.5 picomol/oocyte/min, respectively. High activity of G6PD suggests the pentose phosphate shunt concerned with steroidogenesis is active in the oocy...
Research Interests: Energy Metabolism, Female, Animals, Rats, Microchemistry, and 4 moreOocytes, Gonadotropins, ovum, and hexokinase
The steroid hormone has an important role in the early stages of reproduction. There has been abundant histochemical evidence that oocytes contain steroid hormones and are able to synthesize these hormones. But there have been few methods... more
The steroid hormone has an important role in the early stages of reproduction. There has been abundant histochemical evidence that oocytes contain steroid hormones and are able to synthesize these hormones. But there have been few methods of analyzing one oocyte biochemically because it is too small and light. In order to study steroidogenesis in the oocyte, a microassay method sensitive enough to analyze the enzyme activities in one oocyte was developed using enzymatic cyling for amplifying the reaction product to 10,000-fold. An oil-well technique and a microtube method were applied in the assay for achieving the reaction in a medium as small as 1.0 to 5.0 microliters under a stereomicroscope. Immature Wistar rats were superovulated by PMS-hCG administration. Oocytes were collected by puncturing the follicle and flushing the tube. They were freeze-dried after washing to remove cumulus cells. The dry weight of one oocyte was 51.2 +/- 6.2 ng in a quartz fiber fishpole balance. The a...
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The physiological importance of EGF in the development of the mouse mammary gland during pregnancy and in spontaneous mammary tumorigenesis has been documented by a series of experimental results presented herein. In our study, we have... more
The physiological importance of EGF in the development of the mouse mammary gland during pregnancy and in spontaneous mammary tumorigenesis has been documented by a series of experimental results presented herein. In our study, we have taken a variety of experimental approaches including radioimmunoassay of EGF in the submandibular gland and plasma, mammary gland organ/cell culture, EGF receptor assay, sialoadenectomy and treatment with EGF and EGF antibodies to assess the role of EGF in the mammary gland. In particular, studies employing sialoadenectomy and EGF replacement have provided valuable information concerning the function of EGF in the body. These studies are possible in the mouse system because the submandibular gland serves as a major source of circulating EGF and also because purified mouse EGF is available commercially. Our work on the biological, endocrinological, and physiological aspects of EGF in normal and neoplastic growth of the mammary gland should be useful fo...
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In female nude mice, epidermal growth factor (EGF) was present at a mean concentration of 42.8 +/- 16.9 (SD) ng/mg wet tissue in the submandibular gland and 0.28 +/- 0.13 ng/ml in the plasma. Sialoadenectomy (removal of the submandibular... more
In female nude mice, epidermal growth factor (EGF) was present at a mean concentration of 42.8 +/- 16.9 (SD) ng/mg wet tissue in the submandibular gland and 0.28 +/- 0.13 ng/ml in the plasma. Sialoadenectomy (removal of the submandibular glands) decreased circulating EGF to undetectable levels (less than 0.1 ng/ml). The possible role of EGF in transplantation and growth of mouse mammary tumors in nude mice was examined by sialoadenectomy, anti-EGF treatment, and EGF replacement therapy. The success rate of transplantation of a spontaneous mouse mammary tumor into nude mice was 55% in normal females and 17% in sialoadenectomized animals. Anti-EGF treatment of sialoadenectomized mice completely abolished the implantation of the tumor. Daily administration of EGF at a dose of 5 micrograms per mouse to both normal and sialoadenectomized animals enhanced the success rate of tumor implantation to more than 80%. Sialoadenectomy and/or anti-EGF treatment of tumor-bearing nude mice reduced t...
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The concentration of epidermal growth factor in the submandibular gland and plasma of female mice increased substantially during pregnancy. Pregestational sialoadenectomy (removal of the submandibular glands) attenuated the rise in plasma... more
The concentration of epidermal growth factor in the submandibular gland and plasma of female mice increased substantially during pregnancy. Pregestational sialoadenectomy (removal of the submandibular glands) attenuated the rise in plasma epidermal growth factor during gestation and reduced the number of mice completing a term pregnancy by approximately 50%. Epidermal growth factor replacement therapy given to these mice during pregnancy improved the outcome of complete pregnancy to 86%. The administration of anti-epidermal growth factor antiserum in a daily dose of 50 or 100 microliter to sialoadenectomized pregnant mice increased the percentages of abortion to 67 and 100, respectively. These results suggest that epidermal growth factor may be necessary for the normal course of pregnancy.
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Arachidonic acid metabolism and prostanoid synthesis were investigated using [14C]-arachidonic acid (AA) in human endometrium obtained at different phases of the ovarian cycle and decidua in early pregnancy. Prostaglandins (PG) identified... more
Arachidonic acid metabolism and prostanoid synthesis were investigated using [14C]-arachidonic acid (AA) in human endometrium obtained at different phases of the ovarian cycle and decidua in early pregnancy. Prostaglandins (PG) identified in endometrium and decidua were PGE2 and PGF2 alpha. The capacity for the production of PGE2 and PGF2 alpha was higher in the secretory phase of endometrium than in the proliferative phase, and the maximum formation of PGE2 and PGF2 alpha was found in the mid secretory phase and in the late secretory phase, respectively. However, the production of PGs was markedly suppressed in decidua. On the other hand, more than 70% of [14C]AA was incorporated into total neutral lipids, whereas less than 22% was incorporated into glycerophospholipids in both endometrium and decidua. Secretory endometrium showed a higher uptake of [14C]AA into glycerophospholipids than did proliferative endometrium, whereas the incorporation into neutral lipids was lower in secre...