Testosterone substitution with a new transdermal, hydroalcoholic gel applied to scrotal or non-scrotal skin: a multicentre trial.

OBJECTIVE: Testosterone-containing gels have improved testosterone substitution therapy, but they are associated with the risk of interpersonal transfer. Therefore, we tested a new hydroalcoholic 2.5% testosterone gel (TGW), which was removed by washing 10 min after administration. DESIGN: The gel was applied to scrotal or non-scrotal skin in comparison to two 2.5 mg Androderm patches in a randomised, three-arm, parallel-group, controlled multicentre trial over a period of 24 weeks. We included symptomatic hypogonadal men whose morning testosterone levels were <10 nmol/l. Either 1 g TGW was applied to scrotal skin (n = 54) or 5 g to non-scrotal skin (n = 56) once daily; the patch group (n = 52) applied two patches/day. Dose titration was allowed. RESULTS: Whereas serum testosterone levels and the pre-post changes of the areas under the curve of testosterone and free testosterone between weeks 0 and 24 indicated equivalent treatment success for the patch and scrotal groups, the dermal gel group was significantly superior to the other two groups. Questionnaires on sexual function, mood and quality of life did not differ significantly between study groups, nor were prostate volume, prostate-specific antigen (PSA) levels and prostate symptoms different. However, tolerability was much better in the gel groups than the patch group. CONCLUSION: Efficacy, safety and tolerability suggest TGW as a favourable treatment for hypogonadal patients.

Mosaic status in lymphocytes of infertile men with or without Klinefelter syndrome.

BACKGROUND: Gonosomal aneuploidies such as Klinefelter syndrome (47,XXY) are the most frequent chromosomal aberration in infertile men. Normally the chromosomal status of patients is detected by karyotyping of up to 20 metaphase spreads of lymphocyte nuclei, whereby low grade mosaicism may be overlooked. To test whether Klinefelter patients with 47,XXY karyotype or infertile men with 46,XY karyotype represent gonosomal mosaicisms, we performed meta- and interphase fluorescence in situ hybridization (FISH) on 45 men. METHODS AND RESULTS: A total of 400 interphase and 40 metaphase lymphocyte nuclei per patient were scored after hybridization with DNA probes specific for chromosomes X and Y, and chromosome 9 as a control. On the basis of conventional karyotype, hormone levels and clinical appearance, patients were subdivided into 18 Klinefelter syndrome patients with 47,XXY (group I), 11 Klinefelter syndrome-like patients with normal karyotype, 46,XY (group II) and six non-Klinefelter-like infertile patients with normal 46,XY karyotype (group III). Ten normal men (group IV) served as controls. Testicular volume in the Klinefelter group I was smaller compared with group II (P = 0.016), group III (P < 0.001) and group IV (P < 0.001). In addition, testicular volumes in group II were lower compared with group III and group IV (P < 0.004). No significant differences between the aneuploidy rate analysed by FISH in interphase nuclei and metaphases were found in either single patients or groups. Patients with Klinefelter syndrome, 47,XXY (group I) or with symptoms similar to those in Klinefelter patients 46,XY (group II) showed a similar aneuploidy rate (group I 7.1 +/- 4.0% and group II 4.6 +/- 3.4%) and two 47,XXY patients with a high prevalence for normal 46,XY lymphocytes had sperm in their ejaculate. However, in general, no correlations between FISH mosaic status and serum hormone parameters, nor with ejaculate parameters were found. CONCLUSIONS: The results suggest that 47,XXY patients with an increased incidence of XY cells (average of 4.2 +/- 2.3) may have a higher probability of germ cells as we found sperm only in the ejaculate of Klinefelter syndrome patients with mosaic 46,XY cells (6.0 and 7.0%). On the other hand, 46,XY patients with mosaic sex chromosome aneuploidies detected by FISH analysis more often show symptoms of hypogonadism phenotypically resembling Klinefelter syndrome.

Case report: natural transmission of an AZFc Y-chromosomal microdeletion from father to his sons.

Y-chromosomal microdeletions, associated with oligozoospermia or azoospermia, are usually de novo deletions in the affected patients. We report here the rare case of an affected father who transmitted a Y-chromosomal microdeletion to at least two of his three sons naturally and who also fathered a daughter. The extent of the deletion, which was determined with new STS-primers and covers 3.5 Mb, was identical in the father and his azoospermic sons. To determine any possibly modifying influence of other genes involved in spermatogenesis, we analysed two polymorphisms of the DAZL gene, the autosomal homologue of the deleted DAZ gene. DAZL and DAZ might be functionally related to each other. However, we found identical polymorphisms in exon 2 and 3 of the DAZL gene, in both father and his sons, corresponding to the most prevalent genotype in fertile men. Thus, other genes or environmental factors must modify spermatogenesis in men with identical Y-chromosomal microdeletions.

The relationship between placental cadmium, zinc, and copper.

A number of interactions between the essential metals zinc (Zn) and copper (Cu), and the toxic metal cadmium (Cd), have been described in animal, but not in human tissues. The purpose of this study was to determine whether Cd levels are directly related to Zn or Cu levels in the human placenta at term, and whether this relationship is affected by parity or smoking. Atomic absorption spectroscopy was used to determine Cd, Zn and Cu in perfused placental cotyledons from 292 low-risk parturients. Plasma thiocyanate levels were used to determine smoking status. Linear regression and repeated measures analysis of variance (ANOVA) were used to examine relationships between the elements and the effects of parity and smoking status. Results show significant correlations between placental Cd and both Zn (r-0.41; p < 0.01) and Cu (r-0.35; p < 0.01), but only in multiparous patients. These relationships were not altered by smoking. These results suggest that Cd-Zn and Cd-Cu interactions occur in the placenta at "normal" levels of Cd exposure and over a very short time period.

Smoking alters the relationship between maternal zinc intake and biochemical indices of fetal zinc status.

Maternal smoking impairs fetal zinc status. This study was designed to clarify the effect of smoking on the relationship between maternal zinc intake and zinc status in mother and fetus. Zinc was measured with atomic-absorption spectroscopy. Statistical analyses consisted of descriptive statistics, simple correlations, and stepwise multiple regression. The results suggest that maternal plasma zinc, red blood cell zinc, and alkaline phosphatase at term are not related to maternal zinc intake. In the nonsmoking parturient both cord-vein plasma zinc and cord-vein alkaline phosphatase activity are positively related to maternal zinc intake. In the smoking parturient there is no relationship between maternal zinc intake and fetal zinc status except for a negative relation with cord-vein plasma zinc. Relations between maternal zinc intake and placental zinc can be shown with stepwise-multiple-regression techniques. The data suggests that maternal zinc intake is related not to maternal zinc status but to fetal zinc status in a normal pregnancy. The relation is altered in the pregnancy complicated by smoking.

Effect of ranitidine on bupivacaine disposition.

This study was undertaken to determine the effect, if any, of ranitidine on bupivacaine disposition in 28 women undergoing cesarean section. Before epidural anesthesia, ranitidine (50 mg IM) or sodium citrate (30 mL orally) was administered to groups of 14 parturients each. Ranitidine was administered 2 h before epidural anesthesia and sodium citrate was administered 10 min before the epidural. Maternal plasma samples were collected after epidural anesthesia with bupivacaine. A total of 15 maternal plasma samples were taken from the time of administration of epidural anesthesia up to 180 min. Postpartum plasma and urine samples were also collected from both mothers and neonates. Plasma samples were collected up to 48 h postpartum at intervals of 12, 24, and 48 h. Urine samples were collected at six 6-h intervals up to 36 h postpartum. A two-way analysis of variance with repeated measures demonstrated that there was no significant difference in bupivacaine levels between the maternal plasma curves of the ranitidine and the control groups. At the time of delivery, plasma levels of bupivacaine and its N-dealkylated metabolite PPX (2,6-pipecolylxylidine) were no different in the mothers or neonates of either group. There was no significant difference in plasma protein binding of bupivacaine in the presence of ranitidine. The excretion rates of bupivacaine and PPX were not measurably influenced by ranitidine. The amount of bupivacaine excreted, the amount of metabolite excreted, and the percentage of drug excreted as metabolite in maternal urine were not significantly different. These data indicate that there is no measurable effect of ranitidine on the disposition of bupivacaine in parturients.

Structural determination of the conjugated metabolites of ritodrine.

Ritodrine is a beta-2 adrenergic agonist which is used clinically for the management of preterm labor. Since ritodrine is resistant to the action of monoamine oxidase and catecholamine-O-methyltransferase, conjugation is a major route of metabolism. Glucuronide and sulfate conjugates of ritodrine are found in maternal urine. However, the structure of these metabolites has not been determined. The purpose of this study was to determine the structure of these conjugates. Urine from patients on ritodrine therapy was purified by QAE Sephadex ion exchange chromatography. The partially purified conjugates were derivatized and analyzed by GC/MS. The data did not indicate an exclusive site of conjugation. Analysis of both the glucuronide and sulfate conjugates indicates that either of the two phenolic hydroxyl groups may be involved in the formation of conjugated metabolites. However, conjugation of the [2-(p-hydroxyphenyl)-2-hydroxy-1-methylethyl]amine phenolic hydroxyl is more prevalent for both conjugates. This phenolic hydroxyl group is unique since it is located on the portion of the ritodrine molecule which more closely resembles the structure of endogenous catecholamines.

The effect of race on serum ferritin during parturition.

The purpose of this study was to determine whether differences in ferritin levels due to race were large enough to alter interpretation of ferritin test results during pregnancy. Patients were screened for hemoglobinopathies and other diseases known to affect ferritin levels. Maternal blood samples were obtained at delivery and analyzed for hemoglobin, hematocrit, and ferritin. One hundred thirty-four white and 69 black parturients were studied. Race was found to significantly affect serum ferritin levels p less than 0.001). Whereas blacks had a mean hemoglobin level 0.6 g/dl lower than whites, their mean serum ferritin level was 7.6 ng/ml higher (18.97 +/- 13.6 vs 11.41 +/- 9). No differences were found in the number of red blood cells, smoking status, or most other clinical variables. The mean serum ferritin level of anemic black parturients was higher, although not significantly different, than that of white nonanemic parturients (14.2 +/- 9.5 vs 12.1 +/- 9.4 ng/ml). Furthermore, increasing parity significantly decreased serum ferritin in both races (p less than 0.004). This was not due to differences in the interval between pregnancies. The results show conclusively that black parturients have significantly higher ferritin levels than white parturients. Therefore, different norms need to be established for blacks and whites if ferritin is used to screen for anemia during pregnancy.

Transient maternal hypotension following epidural anesthesia.

Transient maternal hypotension following regional anesthesia can lead to significantly lower umbilical cord pH values. Although this acidosis has not been found to be clinically significant, acidosis may increase the placental transfer of local anesthetic agents as a result of "ion trapping." The purpose of this study was to examine the pharmacologic and clinical consequences of transient maternal hypotension following epidural anesthesia with 0.5% bupivacaine before cesarean section. Patients were divided into two groups based on the development of maternal hypotension, defined as a systolic blood pressure less than 100 torr or a decrease of 30% or more from the preanesthetic level. Thirteen patients (33%) developed hypotension that was corrected within 2.1 +/- 1.8 min. The pH of umbilical cord venous and arterial blood and the concentration of bupivacaine were significantly lower (P less than 0.05) in neonates of mothers in the hypotensive group than in neonates of mothers that did not develop hypotension. The results show, however, that transient maternal hypotension following epidural anesthesia does not lead to a greater placental transfer of bupivacaine due to "ion trapping" even though neonatal cord blood pH decreases.

Zinc, cadmium, and hypertension in parturient women.

Zinc deficiency and cadmium toxicity have both been implicated in hypertension during pregnancy. The goals of this study were twofold: first, to assess the different zinc indices (plasma, red blood cell zinc, heat-labile alkaline phosphatase, and placental zinc) in normotensive and hypertensive parturients to determine whether they are altered in the different types of hypertension that occur during pregnancy; second, to assess whole-blood cadmium and placental cadmium with regard to hypertension and zinc status. Patients were diagnosed as having chronic hypertension or preeclamptic toxemia and were then further divided into groups on the basis of smoking status. Each patient was matched with a normal control subject based on age, parity, and smoking status. Forty-three hypertensive patients and their matched control subjects were studied. No differences were found in the various zinc indices between chronic hypertensive parturients and normal control subjects. However, in parturients with preeclamptic toxemia, the plasma zinc level was 19% lower than in control subjects (p less than 0.02); these patients had the lowest plasma zinc level of the three groups. Placental zinc was also 12% lower in patients with preeclamptic toxemia than in control subjects (p less than 0.04). Whole-blood cadmium and placental cadmium levels did not differ between control subjects or hypertensive patients. However, a significant positive correlation was found between whole-blood cadmium and plasma zinc levels in preeclamptic toxemia (r = 0.53; p less than 0.05). The results support a marginal zinc deficiency in parturients with preeclamptic toxemia but not in those with chronic hypertension. The role of cadmium in the cause of preeclamptic toxemia remains unclear.

Intravenous, deltoid, or gluteus administration of meperidine during labor?

It has been suggested, but not well verified, that drug absorption from traditional intramuscular injection sites is altered during labor. This study tested the hypothesis that absorption of meperidine from the gluteus muscle would be impeded when compared with deltoid or intravenous administration. Five patients in labor were given 50 mg intravenously, 10 were given 50 mg in the gluteus muscle, and five were given 50 mg in the deltoid muscle. Five nonpregnant subjects served as their own controls for all three routes of administration. Blood samples were obtained at intervals after injection, meperidine was determined by gas chromatography/mass spectrometry, and mean plasma levels of meperidine versus time after administration were plotted. Repeated measures analysis of variance was used to determine whether the curves were significantly different from 30 to 150 minutes. Maternal plasma levels after gluteus injection were significantly lower than those after intravenous injection (F[1,8] = 10.53; p less than 0.01). In nonpregnant subjects, drug levels were not significantly different from 30 to 150 minutes after either gluteus or intravenous injection. Plasma levels after deltoid injection were always higher than those after gluteus injection in both pregnant and nonpregnant subjects (F[1,8] = 9.7; p less than 0.02; F[1,8] = 14.5; p less than 0.004). These findings support impaired absorption of drugs from the gluteus muscle and suggest the deltoid muscle as the favored intramuscular site during labor.

Maternal and neonatal urinary excretion of sulfate and glucuronide ritodrine conjugates.

Ritodrine is a beta 2-adrenergic agonist that is used clinically for the management of preterm labor. The beta 2 activity of ritodrine produces the relaxation of smooth muscles and is believed to act directly on the beta 2-receptors of the myometrium. Reports in the literature suggest that ritodrine is inactivated by sulfate and glucuronide conjugation, but this has not been verified in humans. Studies on animal models indicate that the sulfate conjugate is a major urinary metabolite of ritodrine. Recent investigations of maternal and neonatal urinary excretion of ritodrine indicate that 80% to 90% of the drug is in the form of conjugates. The purpose of this study was to determine the nature of these conjugates. Our study indicates that both the mother and neonate excrete glucuronide and sulfate conjugates of ritodrine. The sulfate conjugate accounts for 45% of maternal excretion and 66% of neonatal excretion; the glucuronide conjugate accounts for 38% and 23% of maternal and neonatal excretion, respectively. Significantly different metabolic profiles suggest that the neonate may be capable of forming conjugated metabolites of ritodrine.

The effect of maternal smoking on the relationship between maternal and fetal zinc status and infant birth weight.

We have previously reported a trapping of zinc in the placenta directly related to circulating cadmium that comes from cigarette smoke. The purpose of this study was to examine in detail the effect of smoking on (a) the relationship between maternal and fetal zinc status and (b) the relationship between zinc status and birth weight. One hundred and eighteen smokers and 172 nonsmokers without any medical complications during pregnancy were studied. Atomic absorption spectroscopy was used to assess zinc status in maternal and cord vein plasma and red blood cells. Plasma alkaline phosphatase was also determined as an index of zinc status. Thiocyanate was used as an index of smoking status. The data were analyzed using univariate correlations and repeated measures analysis of variance. Infants of smokers had a statistically significant decrease in plasma zinc (5%), alkaline phosphatase (13%), and in cord vein RBC zinc (12%). Furthermore, the results showed an altered relationship between maternal and fetal indices of zinc status and zinc status and birth weight due to maternal smoking. The infant of the nonsmoking mother appears to be able to maintain adequate zinc status due to depletion of maternal zinc. However, it appears that the infant of the smoking mother may be marginally zinc deficient. These findings support studies of zinc supplementation in the pregnancy complicated by smoking.

PIP: The effect of cigarette smoking on, 1st, the relationship between maternal and fetal zinc status, and 2nd, the relationship between zinc status and birthweight was investigated in 118 smokers and 172 nonsmoking controls. Zinc status in maternal and cord vein plasma and red blood cells was assessed by means of atomic absorption spectroscopy. Plasma alkaline phosphatase was also used as an index of zinc status, while thiocyanate was used as an index of smoking status. The data indicated an altered relationship between zinc status in mother and fetus and an altered relationship between plasma and cord vein red blood cell zinc and birthweight due to maternal smoking during normal pregnancy. In smokers, there were significant positive correlations between maternal and cord vein heat labile alkaline phosphatase, between maternal and cord vein red blood cell zinc, between maternal and fetal plasma zinc, and a significant negative correlation was found between maternal plasma zinc and fetal red blood cell zinc. At each birthweight interval, infants of nonsmokers have more red blood cell zinc in their cord blood than their mothers. Also found was an inverse relationship between maternal plasma zinc and birthweight in smokers, suggesting that zinc is unable to reach the smoker's fetus. In contrast, infants of nonsmokers appear to be able to maintain adequate zinc status due to depletion of maternal zinc. It is possible that the inability of zinc to cross the placenta in cases of maternal smoking can be partially ameliorated by a more adequate maternal zinc status. Thus, zinc supplementation in smokers is worthy of consideration during pregnancy.

Disposition of intrapartum narcotic analgesics in monkeys.

Maternal-fetal disposition and neonatal respiratory depressant effect of narcotic analgesics were studied by administration of meperidine (2 mg/kg, IV) or alfentanil (IV infusion, 0.1 mg/kg total dose) during labor in rhesus monkeys. Fetal/maternal plasma ratios were lower for alfentanil, the more highly protein-bound drug (fetal/maternal ratio 0.20 at birth versus 0.46 for meperidine). However, elimination of alfentanil was delayed in the neonate. Indeed, plasma concentrations of alfentanil increased during the first 2 postnatal hours, indicating a compartmental shift from tissues to circulation in the neonate. As regards respiratory depression, six of ten narcotic-treated monkeys had suboptimal (less than 60 breath/min) respiratory rates at birth. Respiratory rate was negatively correlated with cord vein normeperidine and meperidine levels; the strongest correlation was with normeperidine (r = -0.84, P less than 0.01). Neonatal normeperidine elimination in the postnatal period was prolonged, as has also been observed in humans. These studies serve as a basis for comparing the neonatal neurobehavioral effects of the two analgesics and support the use of the rhesus monkey as an animal model to further understanding of the effects of narcotic analgesics on neonatal respiration.

Associations between placental cadmium and zinc and age and parity in pregnant women who smoke.

We have previously shown that the ratio of placental zinc to placental cadmium (Zn/Cd ratio) is positively related to infant birth weight in pregnant smokers. Clinical studies have reported that older pregnant smokers are at higher risk for impaired fetal growth than younger pregnant smokers. This study examines the relationships among placental cadmium, placental zinc, placental Zn/Cd ratio, age, and parity in 98 smokers and 151 nonsmokers. Atomic absorption spectroscopy was used to analyze cadmium and zinc. Thiocyanate was used as an index of smoking status. The data were analyzed using univariate correlation and repeated-measures analysis of variance. The results showed that increased parity is related to increased levels of placental cadmium in smokers, and decreased placental zinc in smokers and nonsmokers. Age is inversely related to the Zn/Cd ratio in both smokers and nonsmokers; moreover, the oldest nonsmokers have a higher ratio than the youngest smokers. These results are consistent with a depletion of body zinc stores with increasing parity and the long half-life of cadmium in the body. The data explain in part the clinical finding that smoking during pregnancy is more harmful in older women.

Zinc status, pregnancy complications, and labor abnormalities.

Maternal plasma zinc levels, red blood cell levels, and serum alkaline phosphatase activity were used as indices of zinc status in 279 pregnant women at delivery and were compared with the incidence of complications during the antenatal period and major dysfunctional labor patterns. The median values for plasma zinc, red blood cell zinc, and alkaline phosphatase were used as cutoff points to subdivide the patient population into "low" and "high" groups. Low levels of maternal plasma zinc were associated with more complications in the antenatal or intrapartum periods than maternal levels of either alkaline phosphatase or red blood cell zinc. Plasma zinc levels less than the median value were more commonly associated with mild toxemia (p = 0.02), vaginitis (p = 0.01), and postdates (p = 0.01) in the antenatal period. During the intrapartum period, low plasma zinc levels were associated with a prolonged latent phase (p = 0.05), a protracted active phase (p = 0.04), labor greater than 20 hours (p = 0.03), second stage greater than 2.5 hours (p = 0.01), and cervical and vaginal lacerations (p = 0.02). Low levels of maternal alkaline phosphatase were strongly associated with a history of previous stillbirth (p = 0.0005). A low maternal red blood cell zinc level was not associated with complications during either period. Since a low plasma zinc level is a valid predictor of pregnancy complications and abnormal labor, the results suggest that plasma zinc screening, as part of the patient's antenatal workup should be evaluated.

Neonatal neurobehavior after epidural anesthesia for cesarean section: a comparison of bupivacaine and chloroprocaine.

Reports of whether or not bupivacaine affects neonatal neurobehavior have been contradictory. The purpose of this study was to test the hypothesis that scores on the Brazelton Neonatal Behavioral Assessment Scale (BNBAS) after epidural anesthesia with bupivacaine for cesarean section would not be different than those after chloroprocaine. Furthermore, if there were any effects, it was hypothesized that they would be related to cord blood levels of the drug. Fifty-five healthy mother/infant pairs were studied. Clinical characteristics, pharmacologic data, and BNBAS scores were obtained and analyzed using statistical techniques that included t-tests, repeated measures analysis of variance, and stepwise multiple regression. The results indicate that infants in the bupivacaine group do significantly better than those in the chloroprocaine group in the orientation cluster of the BNBAS (F[1,49] = 22, P less than 0.001); this cluster reflects higher cortical functioning. Furthermore, there was improvement in the bupivacaine group in the regulation of state cluster with age, whereas there was no improvement in the chloroprocaine group (F[1,53] = 4.34, P less than 0.01). This study suggests that performance on the BNBAS after exposure to bupivacaine is better than that after exposure to chloroprocaine.