Decreased pregnancy rate per embryo transfer in women undergoing assisted reproductive technology after abdominal trachelectomy: A retrospective study.

OBJECTIVE: Abdominal trachelectomy (AT) is a fertility-preservation surgery for patients with early-stage cervical cancer. Few studies have reported the outcomes of assisted reproductive technology (ART) in patients after AT. The aim of this study was to evaluate the outcomes of ART after AT. STUDY DESIGN: In this retrospective study, we compared the ART outcomes of 13 patients who underwent AT at another hospital prior to undergoing ART at our clinic (T group) and 52 control patients (non-T group) who did not undergo AT prior to ART, selected on the basis of age, time of treatment onset, and serum anti-Müllerian hormone concentrations, matched 1:4, respectively. RESULTS: Cumulative live birth rates were 62% (8/13) and 65% (34/52) in the T and non-T groups, respectively (p = 0.795). The total number of oocyte retrieval cycles was 34 in the T group and 95 in the non-T group. In all oocyte retrieval cycles, no significant differences were noted in the number of oocyte retrievals, rate of fertilization, and presence of good-quality blastocysts (Gardner classification ≥ BB). The total number of embryo transfer (ET) cycles was 55 in the T group and 109 in the non-T group. The pregnancy and live birth rates per ET were lower in the T group than those in the non-T group (pregnancy rate, 20% vs. 39%, p = 0.017; live birth rate, 15% vs. 30%, p = 0.028; respectively). Endometrial thickness before ET was lower in the T group vs. the non-T group: median (range): 7.4 (3.5-14.3) mm vs. 9.0 (5.5-14.9) mm, respectively; p < 0.0001. Multivariate logistic regression models showed that age at oocyte retrieval (adjusted odds ratio [OR], 0.76; 95% confidence interval [CI], 0.66-0.87), use of good-quality blastocysts (adjusted OR, 3.23; 95% CI, 1.20-8.67), and history of AT (adjusted OR, 0.28; 95% CI, 0.11-0.72) were associated with the pregnancy rate per ET. CONCLUSION: The pregnancy rate per ET was lower in patients with vs. without a history of AT. Clinicians should be aware of the longer time to pregnancy in patients who undergo ART after AT.

Injury to the endometrium prior to the frozen-thawed embryo transfer cycle improves pregnancy rates in patients with repeated implantation failure.

AIM: This retrospective cohort study evaluated the effectiveness of injury to the endometrium prior to the frozen-thawed embryo transfer (FET) cycle in patients with repeated implantation failure (RIF) in our clinic. METHODS: Included in this study were 173 patients, aged ≤ 41 years, who failed to become pregnant after repeating fair and/or good embryo transfer more than twice between February 2012 and February 2015. The patients were divided into three groups: Group A (n = 38) underwent soft curettage to the endometrium twice, prior to the FET cycle; Group B (n = 45) underwent hysteroscopy prior to the FET cycle, with no significant factors, such as endometrial polyp; and Group C (n = 90) was the no-treatment group. RESULTS: The clinical pregnancy rate per transfer was found to be statistically significant between Group A at 42.1% (16/38) and Group C at 22.2% (20/90). The crude and adjusted odds ratios (OR) were 2.55 and 2.49 (95% confidence intervals 1.13-5.78, P = 0.03 and 1.01-6.17, P = 0.048) respectively. Group B with only hysteroscopy had a higher pregnancy rate of 35.6% (16/45) than Group C, but showed no statistical significance (P = 0.103). CONCLUSION: These results suggest that injuring the endometrium has a positive effect on pregnancy.

Developmental capacity and implantation potential of the embryos with multinucleated blastomeres.

The presence of multinucleated blastomeres (MNBs) in embryos is associated with poor developmental competence in assisted reproductive technologies. This phenomenon is observed not only in humans but also in other animal species. The purpose of the present study was to investigate the characteristics of embryos with MNBs (MNB embryos) that could be utilized in embryo transfer. The developmental rate of MNB embryos to the blastocyst stage (50.8%) was significantly lower than that of normal embryos (73.3%) (P < 0.05). The clinical pregnancy rates of fresh embryo transfer (ET) using day 2 or day 3 embryos were significantly lower in MNB embryos (5.1%) compared with normal embryos (24.0%) (P < 0.05). In the case of frozen-thawed ET using a single vitrified/warmed blastocyst, however, the clinical pregnancy rate of MNB embryos was close to that of normal embryos (59.1% vs. 52.8%). Thus, the findings of the present study suggest that the frozen-thawed ET of MNB embryos might improve the potential for implantation followed by successful pregnancy.

Effects of antidiabetic treatment with metformin and insulin on serum and adipose tissue adiponectin levels in db/db mice.

Decreased circulating levels of adiponectin, a novel adipose-derived adipocytokine, in obesity possibly contribute to the development of insulin resistance which is a major factor in the pathogenesis of type 2 diabetes. The present study was conducted to examine whether circulating and adipose tissue adiponectin levels are modulated by chronic treatment with metformin and intensive treatment with insulin in murine models of obesity and type 2 diabetes, db/db mice with a C57BL/KsJ genetic background. Nine-week-old male db/db mice were treated with metformin, insulin, and vehicle for 4 weeks. Expectedly, metformin treatment led to inhibition of weight gain and improvement of hyperinsulinemia. Insulin treatment lowered fasting blood glucose levels to normal values, although it sustained hyperinsulinemic state. However, after 4 weeks of treatment, serum adiponectin levels were not significantly elevated in either metformin-treated or insulin-treated db/db mouse group (14.2 +/- 0.7 and 16.7 +/- 1.0 microg/ml, respectively) compared to vehicle-treated group (14.9 +/- 0.6 microg/ml). Similarly, adipose tissue adiponectin levels determined by Western blot analysis were not increased in either metformin-treated or insulin-treated group relative to vehicle-treated group. Recent studies have shown that adiponectin possibly has the same physiological effects on lipid and glucose metabolism that metformin has. Therefore, an elevation in blood concentration of metformin following the treatment might lead to suppression in adiponectin synthesis in adipose tissue, independent of inhibition in weight gain and improvement in hyperinsulinemia by metformin treatment. The present results indicate that adiponectin is not involved in the mechanism by which metformin treatment enhances insulin sensitivity. Moreover, our results suggest that adiponectin synthesis in adipose tissue may be suppressed under hyperinsulinemic state sustained by insulin treatment, even though hyperglycemia is markedly reduced. We conclude that antidiabetic treatment with metformin and insulin does not affect circulating and adipose tissue adiponectin levels.

Urinary excretion of transferrin and orosomucoid are increased after acute protein loading in healthy subjects.

BACKGROUND/AIMS: The aim of this study was to elucidate what kind of plasma proteins would change their urinary excretions when the glomerular filtration rate (GFR) was increased. METHODS: We measured urinary excretions of three plasma proteins with different molecular radii (MR) and isoelectric points (pI): albumin, orosomucoid (OM) and transferrin (Tf), after acute protein loading in healthy subjects. RESULTS: Urinary excretion of OM with more anioic charge and smaller MR than albumin, and Tf with more cationic charge and slightly larger molecular weight than albumin, significantly increased in parallel with increased creatinine clearances after acute protein loading. These renal responses returned to basal levels 9 h after protein ingestion. In contrast, increases in urinary excretion of albumin were not observed. CONCLUSION: Because these findings could not be explained by changes in either size or charge selectivity of shunt pores in the glomerular capillary wall, it is suggested that urinary excretion of albumin may have a special property that distinguishes it from other plasma proteins and may be a less sensitive marker to reflect changes in renal hemodynamics than the other plasma proteins.

[A case of pleomorphic TSH-producing pituitary adenoma with calcification].

We reported a rare case of pleomorphic TSH-producing pituitary adenoma with calcification and reviewed the literature. A 25-year-old female was admitted to our hospital with a complaint of anterior neck swelling. An endocrinological examination demonstrated elevated serum levels of free triiodothyronine (FT3: 5.6 pg/ml), free thyroxin (FT4: 2.2 ng/dl), TSH (5.85 microIU/ml), and TSH a-subunit (5.9 ng/ml), whereas a physical examination revealed no goiter. CT scan showed a suprasellar isodensity mass with dense calcification. Contrast-enhanced T1-weighted images revealed a less enhancing tumor extending from the left upper portion of pituitary fossa into suprasellar cistern. The patient underwent gross total removal of the tumor via the right pterional approach. Microscopically, medium-sized to enlarged tumor cells with marked pleomorphism and prominent calcification were observed. The tumor cells displayed positive reaction for TSH (beta-subunit). The MIB-1 index averaged 2.9%. The histological diagnosis was a pleomorphic TSH-producing pituitary adenoma. Postoperatively, the serum levels of FT3, FT4, TSH, and TSH alpha-subunit decreased to normal range. Follow-up MR images showed no evidence of recurrent tumor 3 years after the resection. All of six patients with densely calcified TSH-producing pituitary adenoma, previously reported in the literature, remained well without tumor recurrence. We suggest that this type of TSH-producing pituitary adenoma may be associated with favorable prognosis despite histologically pleomorphic appearance.

Parallel increase in urinary excretion rates of immunoglobulin G, ceruloplasmin, transferrin, and orosomucoid in normoalbuminuric type 2 diabetic patients.

OBJECTIVE: Increased urinary excretions of several plasma proteins with different molecular radii <55 A and different isoelectric points (pI), such as IgG, ceruloplasmin, transferrin, and orosomucoid, have been independently reported to precede the development of microalbuminuria in diabetic patients. We examined whether increases in urinary excretions of these proteins would be in parallel in the same patient. RESEARCH DESIGN AND METHODS: Urinary excretion rates of proteins mentioned above in timed overnight urine samples were evaluated in 61 normoalbuminuric type 2 diabetic patients (group D) aged 40-60 years and in 17 age-matched control subjects (group C). RESULTS: The excretion rates of these proteins were significantly higher in group D than in group C. These exhibited a strong linear correlation with each other and had a weak correlation with the excretion rate of N-acethylglucosaminidase. The excretion rate of alpha2-macroglobulin with large molecular radii of 88 A was not different between groups C and D, nor did they have any correlations with the excretion rates of the other proteins. Creatinine clearance and blood pressure levels in group D were significantly higher than those in group C. CONCLUSIONS: In normoalbuminuric diabetic patients, excretion rates of plasma proteins with molecular radii <55 A increased in parallel with each other. In view of our previous finding that urinary excretions of these plasma proteins selectively increased in parallel with enhanced glomerular filtration rate after acute protein loading, the present finding may be explained by renal hemodynamic changes, such as increased intraglomerular hydraulic pressure.

Urinary adiponectin excretion is increased in patients with overt diabetic nephropathy.

Adiponectin, a novel adipose-derived adipocytokine, has beneficial effects not only on improvement of insulin sensitivity but also on mitigation of vascular damage. To evaluate whether adiponectin is implicated in the pathogenesis of diabetic nephropathy characterized by microvascular damage, we examined urinary and serum adiponectin levels in type 2 diabetic patients with different stages of nephropathy. We first confirmed adiponectin is excreted into urine through Western blot analysis, followed by measurements of urinary and serum adiponectin levels by radioimmunoassay. Interestingly, urinary adiponectin excretion levels were markedly increased in patient group with overt nephropathy relative to the groups without nephropathy and with incipient nephropathy. Surprisingly, serum adiponectin levels were also elevated in patient group with overt nephropathy. Increased urinary adiponectin excretion may result from elevations in circulating adiponectin levels and enhanced filtration of circulating adiponectin through the damaged kidney. Furthermore, adiponectin synthesis in adipose tissue and its secretion into circulating blood may be enhanced to mitigate microvascular damage in the advanced stage of diabetic nephropathy.

Selected single blastocyst transfers maintained pregnancy outcome and eliminated multiple pregnancies.

Background: Transfer of more than one embryo following in vitro fertilization/intracytoplasmic sperm injection cycles have increased pregnancy rate at the cost of increasing the incidence of triplets and twins. It has been proposed that prolonged culture to the blastocyst stage would automatically result in the selection of good quality embryos for transfer and minimize the incidence of triplets and twins. Methods and Results: The objectives of the present retrospective analysis were to examine the pregnancy outcome, multiple pregnancy and related data following: (i) single blastocyst transfer (BT) and double BT; (ii) single BT in patients belonging to different age groups; and (iii) good, fair or poor quality of BT. A total of 260 BT were carried out between August 1998 and July 2002 and they are included in the current study. Sixty of the 260 BT patients received a single BT, and 41 of them received selected single good quality BT (SSBT). The implantation rate has no significant difference between following single BT (53.3%) and double BT (42.8%). No multiple pregnancy occurred following single BT, while significantly higher (P < 0.05) multiple pregnancy rate was observed following a double BT (45.8%). The clinical pregnancy and implantation rates following a single BT were similar (P > 0.05) in patients belonging to <30 years (62.5%), 30-34 years (57.9%) and 35-39 years old (35.8%). Conclusion: Selected single good quality BT maintained pregnancy and avoided multiple pregnancies. It is recommended for patients with a risk for high-order multiple pregnancy. (Reprod Med Biol 2004; 3: 13-18).

Increased urinary excretion of monocyte chemoattractant protein-1 in proteinuric renal diseases.

Monocyte chemoattractant protein-1 (MCP-1) is a chemokine that is produced mainly by tubular epithelial cells in kidney and contributes to renal interstitial inflammation and fibrosis. More recently, we have demonstrated that urinary MCP-1 excretion is increased in proportion to the degree of albuminuria (proteinuria) and positively correlated with urinary N-acetylglucosaminidase (NAG) levels in type 2 diabetic patients. Based on these findings, we have suggested that heavy proteinuria, itself, probably aggravates renal tubular damage and accelerates the disease progression in diabetic nephropathy by increasing the MCP-1 expression in renal tubuli. In the present study, to evaluate whether urinary MCP-1 excretion is increased in the proteinuric states not only in diabetic nephropathy but also in other renal diseases, we examined urinary MCP-1 levels in IgA nephropathy patients with macroalbuminuria (IgAN group; n = 6), and compared the results with the data obtained from type 2 diabetic patients with overt diabetic nephropathy (DN group; n = 23) and those without diabetic nephropathy (non-DN group; n = 27). Urinary MCP-1 excretion levels in non-DN, DN, IgAN groups were 157.2 (52.8-378.5), 346.1 (147.0-1276.7), and 274.4 (162.2-994.5) ng/g creatinine, median (range), respectively. Expectedly, urinary MCP-1 and NAG excretion levels in DN and IgAN groups were significantly elevated as compared with non-DN group. Therefore, we suggest that MCP-1 expression in renal tubuli is enhanced in proteinuric states,irrespective of the types of renal disease, and that increased MCP-1 expression probably contributes to renal tubular damage in proteinuric states.

Association of monocyte chemoattractant protein-1 with renal tubular damage in diabetic nephropathy.

Monocyte chemoattractant protein-1 (MCP-1), is a chemokine that mediates renal interstitial inflammation, tubular atrophy, and interstitial fibrosis by recruiting monocytes/macrophages into renal tubulointerstitium. Recent studies have demonstrated that protein overload in renal tubular cells up-regulates MCP-1 gene and its protein expression. Therefore, we hypothesized that increased expression of MCP-1 in renal tubuli, probably triggered by an increase in the leakage of plasma protein from glomerular capillary to tubular fluid, may contribute to renal tubular damage and accelerate the progression of diabetic nephropathy. To test this hypothesis, we examined urinary excretion levels of MCP-1 and N-acetylglucosaminidase (NAG), a sensitive marker of renal tubular damage, in Japanese Type II diabetic patients with normoalbuminuria (n=29), microalbuminuria (n=25), and macroalbuminuria (n=18). The median urinary excretion level of MCP-1 in patients with macroalbuminuria (394.4 ng/g creatinine) was significantly elevated compared to the levels in patients with normoalbuminuria and microalbuminuria (159.6 and 193.9 ng/g creatinine, respectively). Furthermore, the urinary MCP-1 excretion level was positively correlated with urinary excretion levels of albumin (r=.816, P<.001) and NAG (r=.569, P<.001) in all subjects. These results suggest that MCP-1 is produced in renal tubular cells and released into urine in proportion to the degree of proteinuria (albuminuria), and that increased MCP-1 expression in renal tubuli contributes to renal tubular damage. Therefore, we conclude that heavy proteinuria itself may accelerate the progression of diabetic nephropathy by increasing the MCP-1 expression in renal tubuli.

Increased urinary excretion of N-acetylglucosaminidase in subjects with impaired glucose tolerance.

N-acetylglucosaminidase (NAG) is a lysosomal enzyme produced by renal proximal tubular cells and has been widely used as a marker, which indicates a degree of renal tubular damage. An increase in urinary NAG excretion is though to result from the renal tubular damage. The aim of this study was to evaluate whether even mild hyperglycemia causes an increase in urinary excretion of NAG, which is a renal tubular protein. We examined urinary NAG excretion in overnight urine in 22 Japanese men with impaired glucose tolerance (IGT) for more than two years (IGT group) and 41 healthy control subjects matched in age, gender, BMI and blood pressure (control group). Urinary NAG excretion levels of IGT group and control group were 2.89 (1.23-7.97) and 2.22 (0.60-4.93) U/g creatinine, median (range), respectively. The IGT group showed significantly higher urinary excretion of NAG compared to the control group (p < 0.01). Several studies have indicated that plasma proteins filtered through the glomerular capillary may have intrinsic renal toxicity. Recently, we have reported that urinary excretion of plasma proteins (ceruloplasmin, IgG4 and IgG) with molecular radii of approximately 45-55 A is increased in subjects with IGT compared to healthy control subjects with normal glucose tolerance. Considering the present result together with our recent finding, we suggest that increased urinary excretion of NAG in the mildly hyperglycemic subjects may be due to the adverse effects of the plasma proteins highly filtered through the glomerular capillary on tubular cells.