Azoospermia and Sertoli-cell-only syndrome: hypoxia in the sperm production site due to impairment in venous drainage of male reproductive system.

Sertoli-cell-only (SCO) syndrome, or germ cell aplasia, is diagnosed on testicular biopsy when germ cells are seen to be absent without histological impairment of Sertoli or Leydig cells. It is considered a situation of irreversible infertility. Recent studies have shown that varicocele, a bilateral disease, causes hypoxia in the testicular microcirculation. Destruction of one-way valves in the internal spermatic veins (ISV) elevates hydrostatic pressure in the testicular venules, exceeding the pressure in the arteriolar system. The positive pressure gradient between arterial and venous system is reversed, causing hypoxia in the sperm production site. Sperm production deteriorates gradually, progressing to azoospermia. Our prediction was that, if genetic problems are excluded, SCO may be the final stage of longstanding hypoxia which deteriorates sperm production in a progressive process over time. This would indicate that SCO is not always an independent disease entity, but may represent deterioration of the testicular parenchyma beyond azoospermia. Our prediction is confirmed by histology of the seminiferous tubules demonstrating that SCO is associated with extensive degenerative ischaemic changes and destruction of the normal architecture of the sperm production site. Adequate treatment of bilateral varicocele by microsurgery or by selective sclerotherapy of the ISV resumes, at least partially, the flow of oxygenated blood to the sperm production site and restored sperm production in 4 out of 10 patients. Based on our findings the following statements can be made: (i) SCO may be related in part of the cases to persistent, longstanding testicular parenchymal hypoxia; (ii) germ cells may still exist in other areas of the testicular parenchyma; and (iii) if genetic problems are excluded, adequate correction of the hypoxia may restore very limited sperm production in some patients.

Hormonology: a genomic perspective on hormonal research.

Recent advances in comparative genomics allow a new paradigm for hormonal research. At the centennial of the first use of the term hormone by Ernest Starling, we reflected on the changing approaches in elucidating hormonal signaling mechanisms and highlighted the inadequacy of the term endocrinology, implying remote activation, to describe the diverse modes of hormone actions. Several examples were presented to underscore the power of comparative genomics in the identification of new polypeptide hormones, receptors, and signaling pathways. We propose the use of the term hormonology to more accurately reflect the expanding boundaries of the discipline.

Intramuscular administration of lidocaine or bupivacaine alters the effect of midazolam from sedation to hypnosis in a dose-dependent manner.

We examined the sedative/hypnotic interaction between the administration of intravenous (i.v.) midazolam and intramuscular (i.m.) lidocaine or bupivacaine. Women undergoing gynecological surgery (n = 150) were randomly assigned to 15 dose groups of 10 patients each. Fifty patients received one of five predetermined doses of midazolam for the calculation of its median effective dose (ED50). The remaining patients (n = 100) received i.v. midazolam 0.1 mg/kg following an i.m. injection of either bupivacaine, lidocaine, or saline (control). Three minutes after the i.v. dose, the loss of response to verbal command was evaluated. The ED50 of midazolam was 0.226 mg/kg (95% confidence interval [CI] 18-027; p = 0.03). Both bupivacaine and lidocaine enhanced the effect of midazolam in a dose-dependent fashion. The hypnotic ED50 for bupivacaine and lidocaine was 0.7 mg/kg (95% CI 0.5-1.0) and 3.32 mg/kg (95% CI 2.2-11.7), respectively. The slopes of the dose-response curves were significantly different (p < 0.01). Local anesthetics that are well within the range of clinical use for regional blocks or local infiltration can bring the effect of midazolam from the sedative into the hypnotic range.

Intravenous midazolam significantly enhances the lethal effect of thiopental but not that of ketamine in mice.

Intravenous (i.v.) drug combinations are used in clinical anaesthesia in order to combine the desired effects and minimize toxicity from large doses of single agents. This fundamental assumption has not been systematically evaluated. We examined its validity by testing the influence of midazolam on the lethal effect of i.v. thiopental and ketamine in mice. Dose-response curves were constructed for the lethal effect of i.v. thiopental and ketamine, and for the loss of righting reflex effect by midazolam, in sexually mature male ICR mice weighing 20-40 g. For each curve, six or seven groups of eight to 10 mice each were used. A quarter of the median effective dose (ED50) for loss of righting reflex by midazolam was combined with the two other drugs to deduce dose-response curves for the lethal effect of the combinations. The ED50 for loss of righting reflex by i.v. midazolam was 43.5 mg x kg(-1) (95% confidence interval [CI], 40.4-46.5). The median lethal dose (LD 50) of i.v. thiopental was 50.6 mg x kg(-1) (95% CI, 50.0-54.9) and that of ketamine 42.9 mg x kg(-1) (95% CI, 32.3-52). In the presence of 10 mg x kg(-1) midazolam, the LD50 of thiopental was reduced to 20 mg x kg(-1) (17.7-22.2), but that of ketamine remained 44.4 mg x kg(-1) (37.7-54.9). Midazolam increased the lethal effect of thiopental 2.5-fold, but did not affect that of ketamine. Interactions at the toxic level between commonly used anaesthetic agents may differ from those at the hypnotic or analgesic levels, which should prompt evaluation of such combinations before their introduction to routine clinical use.

Matrix metalloproteinase (MMP)-2 and MMP-9 and their inhibitor, TIMP-1, in human term decidua and fetal membranes: the effect of prostaglandin F(2alpha) and indomethacin.

Degradation and breakdown of gestational membranes and the adjacent decidua are essential processes for the advancement of labour. We have assessed the effect of prostaglandin (PG) synthesis on the expression and activity of matrix metalloproteinase (MMP)-2 and MMP-9 and tissue inhibitor of metalloproteinases (TIMP-1) in fetal membranes at the edge of the placenta and decidua, by using ex-vivo organ culture of the tissues in the absence or presence of PGF(2alpha) (0.1, 1.0 and 10 microg/ml) or a PG synthesis inhibitor, indomethacin (10(-4)-10(-6) mol/l). Conditioned media were assessed for MMP by zymography on gelatin containing sodium dodecyl sulphate-polyacrylamide gels and for TIMP-1 by Western blot analysis. Compared to the membranes, decidua produced significantly more MMP-2 and MMP-9 as well as TIMP-1. PGF(2alpha) caused a 2.4- and 1.9-fold increase in the production of MMP-2 and MMP-9 in the decidua, respectively (P < 0.05), and an 11.3-fold increase of the active form of MMP-2 (62 kDa) which could hardly be detected in basal culture conditions (P < 0.01). PGF(2alpha) decreased TIMP-1 production by 70% in the decidua. The production of MMP-2 and MMP-9 and TIMP-1 by the amniotic and chorionic membranes was not affected by PGF(2alpha). Indomethacin decreased the production of MMP-2 and MMP-9 by 78 and 35% in chorion, and by 70 and 58% in amnion, respectively (P < 0.05), but did not affect production in decidual tissue. Indomethacin increased the production of TIMP-1 in chorion and amnion [by 4.1- and 4.5-fold respectively (P < 0.01)], but had no effect on decidua. Cumulatively, PGF(2alpha) increases decidual gelatinolytic activity. Meanwhile the inhibition of PG production by indomethacin reduces total gelatinolytic activity in fetal membranes, possibly accounting for some of its labour-arresting property.

Can we abandon routine evaluation of serum estradiol levels during controlled ovarian hyperstimulation for assisted reproduction?

OBJECTIVE: To assess whether abandoning measurement of serum estradiol (E2) and spacing ultrasound evaluations at greater intervals had an effect on the results of assisted reproduction technology (ART). DESIGN: A retrospective comparison of two consecutive periods. SETTING: Division of Assisted Reproduction Technology, Department of Obstetrics and Gynecology, Ha'Emek Medical Center, Afula, Israel. PATIENT(S): One thousand nine hundred and eighty-five controlled ovarian hyperstimulation (COH) cycles for ART were initiated during the years 1996 to 1999. INTERVENTION(S): During the first 2 years an intensive follow-up protocol was used that included E2 blood levels measurements. In the next 2 years a less intensive protocol was adopted that did not use E2 measurements. MAIN OUTCOME MEASURE(S): ART results and the rate of ovarian hyperstimulation syndrome (OHSS). RESULT(S): The patients' background characteristics did not differ between the two periods. The cancellation rate was not different (9.8% vs. 7.2%). There was no difference in the duration of stimulation or the amount of gonadotropins used. The number of oocytes retrieved (12.1 +/- 9.3 vs. 9.6 +/- 6.3), fertilization rates (74% vs. 75%), and clinical pregnancy rates (26.2% vs. 27.9%) did not differ. The incidence of severe ovarian hyperstimulation syndrome was not significantly different between the two periods. CONCLUSION(S): Controlled ovarian hyperstimulation for ART can be done reliably without routine, serial serum E2 measurements without compromising the treatment results.

The balance between MMP-9 and MMP-2 and their tissue inhibitor (TIMP)-1 in luteinized granulosa cells: comparison between women with PCOS and normal ovulatory women.

Polycystic ovarian syndrome (PCOS) involves follicular atresia, formation of multiple ovarian cysts and is frequently associated with a higher abortion rate. Follicular development, ovulation, formation of corpus luteum and its regression involve extensive tissue remodelling. Mammalian ovaries express a number of matrix metalloproteinases (MMP) and their tissue inhibitors (TIMP). We assessed the differences in production of MMP-2, MMP-9 and TIMP-1 by cultured luteinized granulosa cells from women with PCOS and normal ovulatory women after ovarian stimulation for IVF treatment. In follicular fluid from women with PCOS, levels of MMP-9 and MMP-2 were higher than the normal group, as was the basal production of these proteins by cultured cells. Basal production of TIMP-1 by cultured cells was not different between PCOS and normal groups. A time-dependent increase in the production of MMP-9 was observed in cells from both normal and PCOS women, although the increase was more pronounced in the latter. Thus the MMP-TIMP balance is shifted toward greater MMP activity in luteinized granulosa cells from women with PCOS.

Diabetes in pregnancy: efficacy and cost of hospitalization as compared with ambulatory management--a prospective controlled study.

BACKGROUND: Pregnant diabetic women are often subjected to frequent and prolonged hospitalizations to assure tight glycemic control, but in recent years attempts have been made at ambulatory control. The financial and social advantages of ambulatory management are obvious, but no report to date has prospectively compared its efficacy with that of hospitalization. OBJECTIVES: To evaluate the efficacy and cost of ambulatory care as compared to repeated hospitalizations for management of diabetes in pregnancy. METHODS: We conducted an 8 year prospective controlled study that included 681 diabetic women, experiencing 801 singleton pregnancies, with commencement of therapy prior to 34 gestational weeks. During 1986-1989, 394 pregnancies (60 pregestational diabetes mellitus and 334 gestational diabetes mellitus) were managed by hospitalization, and for the period 1990-1993, 407 pregnancies (61 PGDM and 346 GDM) were managed ambulatorily. Glycemic control, maternal complications, perinatal mortality, neonatal morbidity and hospital cost were analyzed. RESULTS: There was no difference in metabolic control and pregnancy outcome in women with PGDM between the hospitalized and the ambulatory groups. Patients with GDM who were managed ambulatorily had significantly lower mean capillary glucose levels, later delivery and higher gestational age at induction of labor as compared to their hospitalized counterparts. In this group there were also lower rates of neonatal hyperbilirubinemia, phototherapy and intensive care unit admissions and stay. The saved hospital cost (in Israeli prices) in the ambulatory group was $6,000 and $15,000 per GDM and PGDM pregnancy, respectively. CONCLUSIONS: Ambulatory care is as effective as hospitalization among PGDM patients and more effective among GDM patients with regard to glycemic control and neonatal morbidity. This is not only more convenient for the pregnant diabetic patient, but significantly reduces treatment costs.

Changes in effective and lethal doses of intravenous anesthetics and lidocaine when used in combination in mice.

We studied the interactions between a local anesthetic agent, lidocaine, and two general anesthetic drugs, propofol and ketamine, in mice. We used two end points: hypnosis, reflected by loss of the righting reflex, and death. The ED50 for hypnosis and the LD50 were determined for each drug separately, and a dose-response curve was prepared for each drug, using combinations of propofol-lidocane and ketamine-lidocaine at three different dose ratios. Probit and isobolographic analyses revealed supra-additive (synergistic) interactions between lidocaine and each of the other anesthetic agents regarding both the effective dose and the lethal dose. No significant difference was found between propofol and ketamine regarding the supraadditive effect.

The effect of propofol anaesthesia on oocyte fertilization and early embryo quality.

Propofol, frequently used for i.v. induction of anaesthesia in assisted reproduction procedures, has been suspected of damaging oocytes. Concentrations of propofol have recently been shown to increase in follicular fluid during oocyte retrieval. Our study was designed to assess whether exposure to increasing concentrations of propofol has a measurable effect on in-vitro fertilization, cleavage and embryo development. A cohort of 130 women underwent i.v. anaesthesia using propofol and fentanyl. Time of anaesthesia from i. v. injection of propofol was measured, as were the doses of the two drugs. In 32 women expected to have more than 15 oocytes retrieved, first, middle and last oocytes were cultured separately. The mean time from i.v. injection to first follicle aspiration was 200 s. The mean time for the aspiration of each additional oocyte was 17.6 s. In 10 out of 11 cases where follicular fluid concentrations of propofol were measured, there was an increase from the first to the last follicle, but no difference was found in the ratio of mature to immature oocytes. Nor were any differences found in fertilization, cleavage and embryo cell number. In so far as in-vitro development reflects embryo quality, we conclude that the time elapsed between retrieval of the first and last oocyte does not affect oocyte quality.

Comparison between four immunoassays for growth hormone (GH) measurement as guides to clinical decisions following GH provocative tests.

OBJECTIVE: To compare four assays for the measurement of GH following provocative tests and to assess the projected clinical decisions, which would have been based on their respective results. DESIGN: Multiple assays of serum samples obtained during provocative tests for GH response. SUBJECTS: Forty-seven children with short stature, who underwent clinical evaluation and GH provocative tests. METHODS: All samples were measured by the immunoassay Sorin-RIA (A), which is routinely used in our laboratory. Basal and peak samples were analyzed by three other immunoassays: Sorin-IRMA (B), DPC-RIA (C) and Wallac-DELFIA (D). Results were classified as low, partial and normal GH response, corresponding to <10, 10-17.9 and >18 microIU/ml peak serum GH levels. RESULTS: High correlation was found between individual results by the four kits (r=0.92-0.94). However, the mean peak GH values were significantly different (p<0.0001). Further analysis using paired t-test has shown highly significant differences between the assays (p<0.0001) apart from assays A and B that were not significantly different. Clinical grouping by the four tests was profoundly different: by assay A, 14.9% were judged low response and 57.4% normal; by assay D, 36.2% were low and only 21.3% normal. Kappa statistics measurement demonstrated poor agreement between assays A and D and between B and D. CONCLUSION: As the criteria for the diagnosis of GH deficiency and the indications for GH therapy are based on laboratory GH results, more must be done to ensure uniformity and comparability of the GH assays.

First trimester diagnosis of conjoined twins in a triplet pregnancy after IVF and ICSI: case report.

A case of conjoined twins in a triplet pregnancy after in-vitro fertilization and intracytoplasmic sperm injection is described. The diagnosis was made by high-resolution vaginal sonography, as early as the eighth week of gestation. The third fetus, of different chorionicity, was normal. Selective termination was successfully done at 12 weeks. The possible association between assisted reproduction and conjoined twinning is discussed. The importance of expert early vaginal sonography of pregnancy resulting from assisted reproduction technology is emphasized.

Effects of delaying puberty on bone mineralization in female rats.

The effect of delaying puberty on bone mineralization was studied using female rats as a model. Repeated injections of gonadotrophin-releasing hormone antagonist (GnRHa) were used to suppress the onset of puberty from the age of 6-10 weeks. A group of control female rats was given aqueous solution injections at the same age and for the same duration. The effect of delaying puberty on bone mineralization was examined using dual energy X-ray absorptiometry (DXA) and peripheral quantitative computerized tomography (QCT), both methods being adapted for small animals. Bone mineral parameters were measured at baseline and at the ages of 10, 17 and 24 weeks in total body, femur and spine. Compared to controls, bone mineral content (BMC) and bone mineral density (BMD), as measured by DXA, were significantly decreased in GnRHa-treated rats in total body and femur at 10 and 24 weeks of age (P < 0.05). The results were even more significant after adjusting for weight. After this adjustment, spine BMC and BMD at 10, 17 and 24 weeks were significantly lower in the treatment group (P < 0.05). Trabecular BMD at the distal femur in the GnRHa treated group as measured by peripheral QCT was significantly lower (P < 0.05). However, cortical bone in the mid-femur had higher BMD, concurrent with lower cortical thickness in the treatment group. In conclusion, a delay in the onset of sexual maturation may cause prolonged, possibly irreversible defect in bone mineralization.

Case report: a novel surgical approach to obstructed hemiuterus: sonographically guided hysteroscopic correction.

Unilateral obstruction of a duplicate uterus is very rare. The current recommendation for its correction involves transmural incision of the uterine muscle. A method is presented here that was successfully applied in one patient suffering from this anomaly, using sonographically guided hysteroscopy. This method obviated the need for an extensive operation.

Twice daily versus four times daily insulin dose regimens for diabetes in pregnancy: randomised controlled trial.

OBJECTIVE: To compare perinatal outcome and glycaemic control in two groups of pregnant diabetic patients receiving two insulin regimens. DESIGN: Randomised controlled open label study. SETTING: University affiliated hospital, Israel. PARTICIPANTS: 138 patients with gestational diabetes mellitus and 58 patients with pregestational diabetes mellitus received insulin four times daily, and 136 patients with gestational diabetes and 60 patients with pregestational diabetes received insulin twice daily. INTERVENTION: Three doses of regular insulin before meals and an intermediate insulin dose before bedtime (four times daily regimen), and a combination of regular and intermediate insulin in the morning and evening (twice daily regimen). MAIN OUTCOME MEASURES: Maternal glycaemic control and perinatal outcome. RESULTS: Mean daily insulin concentration before birth was higher in the women receiving insulin four times daily compared with twice daily: by 22 units (95% confidence interval 12 to 32) in patients with gestational diabetes and by 28 units (15 to 41) in patients with pregestational diabetes. Glycaemic control was better with the four times daily regimen than with the twice daily regimen: in patients with gestational diabetes mean blood glucose concentrations decreased by 0.19 mmol/l (0.13 to 0.25), HbA(1c) by 0.3% (0.2% to 0.4%), and fructosamine by 41 micromol/l (37 to 45), and adequate glycaemic control (mean blood glucose concentration <5.8 mmol/l) was achieved in 17% (8% to 26%) more women; in patients with pregestational diabetes mean blood glucose concentration decreased by 0.44 mmol/l (0.28 to 0.60), HbA(1c) by 0.5% (0.2% to 0.8%), and fructosamine by 51 micromol/l (45 to 57), and adequate glycaemic control was achieved in 31% (15% to 47%) more women. Maternal severe hypoglycaemic events, caesarean section, preterm birth, macrosomia, and low Apgar scores were similar in both dose groups. In women with gestational diabetes the four times daily regimen resulted in a lower rate of overall neonatal morbidity than the twice daily regimen (relative risk 0.59, 0.38 to 0.92), and the relative risk for hyperbilirubinaemia and hypoglycaemia was lower (0.51, 0.29 to 0.91 and 0.12, 0.02 to 0.97 respectively). The relative risk of hypoglycaemia in newborn infants to mothers with pregestational diabetes was 0.17 (0.04 to 0.74). CONCLUSIONS: Giving insulin four times rather than twice daily in pregnancy improved glycaemic control and perinatal outcome without further risking the mother.