Is there evidence for preferential delivery of ovarian estradiol to the endometrium?

Objective: To determine the direction of delivery of E₂ in the female pelvis by assessing the ratio of endometrial to serum E₂ in women whose ovaries were stimulated to produce E₂ with women who received exogenous E₂.

Design: Prospective comparative study.

Setting: University-based ART program.

Patient(s): Oocyte donors and recipients of donor oocytes.

Intervention(s): Micronized E₂ administered by the oral or vaginal route and oocyte donation.

Main Outcome Measure(s): Serum and endometrial levels of E₂.

Result(s): Serum E₂ levels were significantly higher in women who underwent controlled ovarian hyperstimulation (COH) and women receiving exogenous E₂ by the vaginal route than in those who received oral E₂. Levels of E₂ in endometrial tissue were similar in women who underwent COH and those receiving oral E₂. Endometrial E₂ levels in women who underwent vaginal administration were significantly higher than those in the oral E₂ or COH groups. The ratio of endometrial to serum E₂ was highest in women who underwent vaginal E₂ and lowest in those undergoing COH.

Conclusion(s): Vaginal administration of micronized E₂ results in preferential absorption of E₂ into the endometrium, consistent with a “uterine first pass” effect. Since endogenous E₂ produced the smallest ratio of E₂ between the endometrium and serum, E₂ produced by the ovaries is not preferentially delivered to the uterus.     

Involvement of prostaglandins in vasopressin stimulation of the human uterus

The involvement of prostaglandins (PG) in the vasopressin (VP) action on the human uterus was investigated in healthy women during three menstruations. Intrauterine pressure was recorded and total pressure area measured. Repeated plasma samples were taken for estimations of arginine(A)- and lysine(L)-VP, 15-keto-13,14-dihydro-PGF_2α and 11- ketotetranor PGF metabolites. During the first menstruation LVP was infused in a dose of 0.08 μg/min. During the second menstruation the infusion of LVP was repeated with the same dose, but 70 min before infusion the women received an oral dose of 500 mg of naproxen. During the third menstruation PGF_2α was administered intravenously in a dose of 25 μg/min. LVP infusion per se caused a significant increase in uterine activity and plasma levels of LVP and PG metabolites. When the women were pretreated with naproxen practically the same uterine activity was induced and closely similar plasma levels of LVP were obtained, but the levels of PG metabolites decreased significantly in comparison with the first series of experiments. Infusion of PGF_2α caused an increase in uterine activity but no change in the plasma levels of AVP. The results indicate that uterine stimulation with VP is possible without an obligatory last step of PG synthesis and release. The results also support the concept that an elevated VP level in primary dysmenorrhoea may be of aetiological importance and is not just released as a 'stress'-hormone because of the dysmenorrhoeic pain.     

Effect of vacuum curettage on the concentrations of plasma 6-keto-prostaglandin Flα and serum thromboxane B2

Summary. Serial plasma samples collected before and after vacuum curettage followed by methylergometrine injection in 10 women were assayed for 6-keto-prostaglandin F_lα (6-keto-PGF^1α). The mean 6-keto-PGF_lα concentration was 97.2 (SE 8.8) pg/ml before cervical dilatation. The concentration rose to 128.2 (SE 13.5) pg/ml (P < 0.10) immediately and to 133.3 (SE 17.8) pg/ml (P < 0.05) 1 h after curettage and returned to the initial value within 5 h. Neither methylergometrine nor anaesthesia, nor non-gynaecological surgery, caused changes in the level of plasma 6-keto-PGF_lα. The capacity of the platelets to produce thromboxane A² during spontaneous clotting of blood did not change during vacuum curettage, anaesthesia and non-gynaecological surgery, nor after methylergometrine. The evidence suggests that the pregnant myometrium and/or intrauterine tissues capable of generating prostacyclin (PGI₂) in vitro may release PG1₂ also in vivo .     

Prevention of postpartum hemorrhage by uterotonic agents: comparison of oxytocin and methylergometrine in the management of the third stage of labor

OBJECTIVES: To determine the efficacy of intravenous oxytocin administration compared with intravenous methylergometrine administration for the prevention of postpartum hemorrhage (PPH), and the significance of administration at the end of the second stage of labor compared with that after the third stage. METHODS: A prospective study was undertaken: two major groups (oxytocin group and methylergometrine group) of 438 women with singleton pregnancy and vaginal delivery were studied during a 15-month period. These two groups were subdivided into three subgroups: 1. intravenous injection (two minutes) group immediately after the delivery of the fetal anterior shoulder, 2. intravenous injection (two minutes) group immediately after the delivery of the placenta, and 3. drip infusion (20 min) group immediately after the delivery of the fetal head. In each group, quantitative postpartum blood loss, frequencies of blood loss >500 ml, and need of additional uterotonic treatment were evaluated. RESULTS: As compared with methylergometrine, oxytocin administration was associated with a significant reduction in postpartum blood loss and in frequency of blood loss >500 ml. The risk of PPH was significantly reduced with intravenous injection of oxytocin after delivery of the fetal anterior shoulder, compared with intravenous injection of oxytocin after expulsion of the placenta (OR 0.33, 95%CI 0.11-0.98) and intravenous injection of methylergometrine after delivery of the fetal anterior shoulder (OR 0.31, 95%CI 0.11-0.85). CONCLUSIONS: Intravenous injection of 5 IU oxytocin immediately after delivery of fetal anterior shoulder is the treatment of choice for prevention of PPH in patients with natural course of labor.     

Effects of oral glucose administration on plasma growth hormone levels in women with polycystic ovary syndrome

Objective: To evaluate the sensitivity of GH secretion to the suppressive effect of oral glucose administration in women with polycystic ovary syndrome (PCOS).

Design: Comparison of the GH response to an oral glucose load in women with PCOS and in weight-matched normally menstruating women (controls).

Setting: Reproductive endocrinology unit.

Patient(s): Eighteen obese and 11 nonobese patients and 10 obese and 10 nonobese controls.

Intervention(s): After an overnight fast, each woman underwent a 75-g, 3-hour oral glucose tolerance test (OGTT).

Mean Outcome Measure(s): Growth hormone, glucose, and insulin responses to OGTT.

Result(s): No significant differences in the glycemic and insulinemic responses were found between the patients and the weight-matched controls. No decrease in plasma GH was observed in both obese and nonobese patients and in obese controls during the OGTT, whereas a significant GH decrease occurred in nonobese controls 60 and 120 minutes after glucose intake.

Conclusion(s): Oral glucose administration was unable to suppress GH levels in nonobese as well as in obese women with PCOS and in obese control women. These data suggest that both PCOS and obesity are associated with a reduced sensitivity of GH secretion to glucose suppression.     

Lack of effect of circulating prostacyclin on contractility of the non-pregnant human uterus

Summary. To study the effect of prostacyclin (PGI₂) on the contractility of the non-pregnant human uterus, the intrauterine pressures in the isthmus and fundus of the uterus were recorded before, during and after intravenous PGI₂ at different phases of two consecutive menstrual cycles in eight women. Infusions of 1–8 ng of PGI₂ mur⁻¹ kg⁻¹ for 20 min caused no changes in intrauterine pressure either during menstruation or any other phase of the cycle when compared with the contractility patterns in the same woman during the control infusion. Thus these data suggest that circulating PGI₂ is not involved in regulating the contractility of the non-pregnant human myometrium.     

Oral Prostaglandin E2in Induction of Labour

Summary: In a randomised study of 207 patients, labour was induced with oral prostaglandin E₂in 107 and intravenous oxytocin (Syntocinon) in the remainder, half in each group with medication alone, the other half with fore-water amniotomy as well. Prostaglandin and oxytocin were found to be more effective when preceded by amniotomy. Once labour was established, the time taken to achieve vaginal delivery was the same with either drug, as also the number of successful vaginal deliveries. There were 6 failed inductions, but no statistical significance in the percentage differences between PGE₂ and oxytocin could be found. The two perinatal deaths which occurred could not be attributed to either drug. Oral PGE₂is therefore as effective as intravenous oxytocin with no observed hypertonus and little side-effects.     

Effects of vaginal progesterone administration on uterine contractility at the time of embryo transfer

Objective: To investigate whether uterine contractility at the time of embryo transer (ET) can be reduced by early onset of luteal support with progesterone administered vaginally.

Design: Prospective analysis.

Setting: Assisted reproduction unit.

Patient(s): Eighty-four women undergoing 84 GnRH-a and FSH/hCG cycles for IVF-ET were studied.

Intervention(s): Vaginal progesterone was randomly started on the day of oocyte retrieval (group A, n = 43) or on the evening of ET (group B, n = 41). On the day of hCG administration and just before ET, 2-minute sagittal uterine scans were obtained by ultrasound and digitized with an image analysis system for assessing uterine contraction frequency.

Main Outcome Measure(s): Uterine contraction frequency.

Result(s): Whereas uterine contraction frequency was similar in both groups on the day of hCG (4.6 ± 0.3 and 4.5 ± 0.3 contractions per minute, respectively), only women in group A showed decreased uterine contraction frequency on the day of ET (2.8 ± 0.2 vs. 4.2 ± 0.3 contractions per minute).

Conclusion(s): Vaginal progesterone administration starting on the day of oocyte retrieval induced a decrease in uterine contraction frequency on the day of ET as compared with preovulatory values. Uterine relaxation before ET is likely to improve IVF-ET outcome by avoiding the displacement of embryos from the uterine cavity.     

Endometrial T-lymphocyte subset infiltration during the ovine estrous cycle and early pregnancy

T-lymphocytes were quantitated within luminal, stromal and glandular areas of ovine endometrium. In experiment 1, ovariectomized (OVX), estrus (E) and day 13 (D13) ewes (six/group) received 500 μg of phytohemagglutinin (PHA) or vehicle in ligated right and left uterine horns, respectively. At 48 h, uteri were removed for the immunohistochemical evaluation of T-lymphocyte subsets. In experiment 2, T-lymphocytes were quantitated within non-pregnant and pregnant uterine horns on day 19. For experiment 1, mean numbers of T₄ and T₈ lymphocytes within luminal and stromal areas of PHA-treated horns were greatest (P < 0.05) for D13 ewes and least (P < 0.05) for E ewes. Numbers of T₆ lymphocytes for these same areas were greatest (P < 0.05) for PHA-treated horns of OVX ewes. Overall, the T₄/T₈ ratio (P < 0.004) and mean number of T₁₉ cells (P < 0.009) were increased by PHA. Numbers of CD45R lymphocytes were not affected by PHA but were greater (P < 0.05) in glandular and luminal than stromal areas. For experiment 2, mean numbers of endometrial T₄, T₆, T₈ and T₁₉ lymphocytes were similar (P> 0.05) between non-pregnant and pregnant horns; however, the number of CD45R lymphocytes was greater (P < 0.05) in endometrial tissue of pregnant than non-pregnant horns. The data indicate that the in vivo response of specific ovine T-lymphocytes to PHA was generally dependent upon reproductive stage and the presence of conceptus tissue influenced the infiltration of CD45R lymphocytes.     

Oral Prostaglandins E2 and F2a in the Induction of Labour

Summary: Oral prostaglandins E₂ and F_2a were used to augment amniotomy in the induction of labour in 173 patients. The success rate was significantly higher with prostaglandin E₂ than with prostaglandin F_2a (89% and 75%, respectively). This was achieved despite a significantly lower incidence of gastrointestinal side effects. No serious maternal or fetal complications occurred with either drug. It is concluded that oral prostaglandin E₂ is more efficient than oral prostaglandin F_2a in the induction of labour.     

Bacterial vaginosis and contraceptive methods

Objective: The aim of this study was to investigate if bacterial vaginosis is associated with the use of specific contraceptives. Methods: The study population consisted of 1314 women attending for periodical preventive examinations at our gynecology unit at the II Institute of Obstetrics and Gynecology of the University ‘La Sapienza’ in Rome. The patient’s history and any current genital symptom were recorded on a structured protocol. Current users of contraceptives were compared with non-users. The χ² test and the t-test were used in the statistical analysis; a stepwise logistic regression analysis was performed to assess the simultaneous effect of more than one variable and to identify for possible confounding factors. Results: Both oral contraceptive and condom use showed a significant protective effect against bacterial vaginosis. Our results also showed a significant increase of BV among IUD users, either before or after adjustments. Conclusions: This study showed a significant negative association between BV and OC and condom use, respectively, and a significant positive association between BV and IUD use. Therefore, we suggest that it is advisable to carry out a systematic microscopic evaluation in order to identify BV for IUD users.     

Progestin modulation of c-fos and prolactin gene expression in the human endometrium.

Objective: To evaluate the influence of the menstrual cycle and the effects of medroxyprogesterone acetate (MPA) on the expression of the protooncogene c-fos and of prolactin (PRL) in the human endometrium in vivo.

Design: Double-blind, placebo-controlled trial.

Setting: Healthy volunteers in an academic research environment.

Patient(s): Regularly cycling women who were not taking hormonal medication.

Intervention(s): Medroxyprogesterone acetate (10 mg/d) or placebo was given for 10 days. Endometrial and blood samples were collected 8–12 hours after the last dose.

Main Outcome Measure(s): Immunohistochemical localization of PRL and c-fos in the endometrium, PRL and c-fos messenger RNA levels in the endometrium, and E₂ and progesterone levels in the serum.

Result(s): Immunoreactive c-fos was concentrated in the nucleus of stromal cells and was observed in a higher proportion of proliferative endometrial specimens compared with secretory specimens from placebo- or MPA-treated patients. The levels of c-fos messenger RNA were greatly reduced in the secretory endometrium regardless of treatment with placebo or MPA, compared with the proliferative endometrium. The c-fos gene expression correlated positively with the serum E₂ levels (r = 0.56) and inversely with the progesterone/E₂ ratio (r = −0.56). The endometrial PRL gene expression (messenger RNA and protein) was rare in the proliferative samples, increased from the early to the mid and late secretory samples, and was increased markedly after treatment with MPA compared with placebo.

Conclusion(s): The differentiation of secretory endometrium is accompanied by decreased c-fos and increased PRL gene expression. The inhibition of c-fos gene expression may contribute to the antiproliferative effect of progestins on the endometrium.     

Characteristics of oral prostaglandin E2-induced labor

Oral prostaglandin E2 appears to play a dual role in human parturition. It induces normal uterine contractions and softens the cervix, thereby decreasing the resistance of the cervix to dilatation. Labor and delivery with oral PGE2 is achieved with less total uterine work when compared with spontaneous nonstimulated labor. This contention is supported by the fact that the rate of cervical dilatation in the active phase of labor is faster (2.73 cm/hr) than that reported by Hendricks et al. for ideal labor (2.12 cm/hour), yet uterine contractility is not increased. Analysis of the composite data of Friedman and Sachtleman in 1974 also shows a more rapid active phase dilatation in the PGE2-stimulated labors (3.3 cm/hour) as compared with spontaneous labor (2.98 cm/hour). Oral PGE2 offers a safe and efficacious alternative to oxytocin for the induction of labor in women. It appears to have a major advantage over oxytocin. The softening effect of PGE2 on the cervix would make this drug an ideal agent for use in patients with low Bishop scores who have medical indications for induction of labor. Regardless of route of administration, prostaglandin E2 is a potent uterine stimulant and must be used with the same precautions and safeguards as intravenous oxytocin.     

Effects of pretreatment with an oral contraceptive on the time required to achieve pituitary suppression with gonadotropin-releasing hormone analogues and on subsequent implantation and pregnancy rates

Objective: To assess the effect of pretreatment with an oral contraceptive (OC) on ovarian cyst formation during pituitary suppression with buserelin acetate.

Design: Prospective randomized trial.

Setting: Academic medical center.

Patient(s): Eighty-three patients who were undergoing IVF-ET treatment.

Intervention(s): Patients in the study group were pretreated with an OC for 14 days starting on the first day of menstruation. The administration of SC buserelin acetate was initiated on the last day of OC administration. Patients in the control group began to receive buserelin acetate on day 2 of menstruation. Hormonal assays and ultrasound scans were performed on the first day of menstruation, and 7, 11, and 14 days after the commencement of buserelin acetate administration. Thereafter, these tests were performed weekly until pituitary suppression was achieved.

Main Outcome Measure(s): Incidence of cyst formation.

Result(s): A cyst developed in 27 patients in the control group (52.9%) and no patients in the study group (odds ratio [OR] = 115; 95% confidence interval [CI] = 10–617). Patients in the study group achieved pituitary suppression faster (median difference [MD] = 7 days; 95% CI = 4–14) and required fewer ampules of gonadotropin (MD = 10; 95% CI = 6–14). They recruited more follicles (MD = 3; 95% CI = 0–5) and had higher pregnancy rates (37.2% versus 33.3%).

Conclusion(s): Pretreatment with an OC abolishes ovarian cyst formation, shortens the time required to achieve pituitary suppression, and decreases gonadotropin requirements without having a negative effect on pregnancy rates.     

Effects of hydrogen peroxide on DNA and plasma membrane integrity of human spermatozoa

Objective: To evaluate the effects of oxidative stress on DNA and plasma membrane integrity of human spermatozoa.

Design: Prospective cohort study.

Setting: University-based, tertiary-care infertility center.

Patient(s): Men (n = 10) undergoing infertility investigation.

Intervention(s): Purified populations of sperm with high motility were separated using Percoll density gradients. Then, spermatozoa were incubated with 0, 10, 100, and 200 μM hydrogen peroxide (H₂O₂) under capacitating conditions.

Main Outcome Measure(s): Motion parameters were assessed by computer analysis. Genomic integrity was examined by the terminal deoxynucleotidyl transferase (TdT)-mediated dUTP nick end–labeling (TUNEL) assay. Plasma membrane integrity was evaluated by the annexin V-binding assay, a measure of phosphatidylserine translocation.

Result(s): Under basal conditions, there was a significant and negative relationship between sperm motility and the percentages of sperm with DNA fragmentation and membrane translocation of phosphatidylserine. After a 2-h incubation, there was a significant, dose-dependent effect of H₂O₂ on motion parameters (decrease) and DNA fragmentation (increase). The percentage of annexin V⁻ live (normal) cells declined significantly as the level of oxidative stress increased. Although the percentages of annexin V⁺ live cells (sperm depicting translocation of phosphatidylserine) and necrotic cells increased at the highest H₂O₂ levels, these changes were not significant.

Conclusion(s): In vitro sperm incubation with H₂O₂ induces DNA fragmentation in a dose-dependent fashion. The sublethal effects of oxidative stress on motion parameters were not significantly associated with membrane translocation of phosphatidylserine.     

Dinoprostone priming of the cervix prior to termination of midgestation pregnancy with sulprostone

Objective: To determine if cervical ripening with the prostaglandin E₂ analogue dinoprostone effectively shortens the induction-to-delivery interval in midpregnancy terminations with sulprostone. Study design: We retrospectively studied 100 women admitted for pregnancy termination at midgestation because of fetal anomalies between September 1989 and January 1993. Three regimens were used: 27 women received intramuscular sulprostone only, 29 women received intravenous sulprostone only, and 44 women received intravenous sulprostone after cervical priming with dinoprostone. Wilcoxon's rank sum test was used for statistical analysis. Results: Dinoprostone priming did not significantly reduce the induction-to-delivery interval in either parous or nulliparous women. However, when divided into first and subsequent pregnancies, we found that primigravidae, but not multigravidae, had an induction-to-delivery interval that was significantly shorter by approximately 10.5 h when pretreated with dinoprostone. Conclusion: Dinoprostone priming of the cervix prior to termination of midgestation pregnancy with sulprostone (Nalador) effectively shortens the induction-to-delivery interval in women in their first pregnancy.     

The antiandrogenic effect of flutamide improves uterine perfusion in women with polycystic ovary syndrome

Objective: To evaluate whether, by blocking androgen action, flutamide can decrease and normalize vascular resistance in the uterine artery in patients with polycystic ovary syndrome (PCOS).

Design: Prospective and controlled study.

Setting: Endocrinological Centre of the Department of Obstetrics and Gynecology of the University of Cagliari, Italy.

Patient(s): Twenty-two patients with PCOS were enrolled in the study and randomly assigned to one of the following two treatments for 3 months: oral administration of flutamide (250 mg twice daily) or placebo.

Intervention(s): Doppler flow measurement of the uterine artery and serum hormone concentration determination during the early follicular phase of the menstrual cycle before treatment and during the third month of treatment.

Main Outcome Measure(s): Pulsatility index (PI) of the uterine artery before and during treatment.

Result(s): The PI of the uterine artery decreased significantly during treatment. No difference was found in patients treated with placebo. Correlation was found only between the PI values of the uterine artery and DHEAS.

Conclusion(s): The low uterine perfusion that characterizes patients with PCOS can be improved by the antiandrogenic effect of flutamide.     

Clinical and subclinical varicocele: a useful distinction?

Objective: The purpose of the study was to establish whether it is useful to make a distinction between clinical and subclinical varicoceles with a view to deciding for treatment or not. Therefore, we compared our results of treatment of clinical vs. subclinical varicoceles. Study design: The changes of semen parameters and the occurrence of pregnancies in 40 infertile men treated for clinical varicocele were compared with those in 46 infertile men treated for subclinical varicocele. The significance of individual semen changes was analysed by paired t-test in both groups and the results of both groups were compared by analysis of covariance. The pregnancy rates were calculated and the life table curves of pregnancy of both groups were compared. Results: There were statistically significant increments in sperm density, motility and morphology both after treatment of clinical and subclinical varicoceles, and these increments did not differ significantly between both groups. The cumulative pregnancy rates after a mean follow-up period of 6.6 years amounted to 42.5% for clinical varicoceles and to 39.1% for subclinical varicoceles and the life table curves of pregnancy ran a rather similar course in both groups. Conclusion: We conclude that there is no reason to emphasize the palpatory findings in infertile men with varicocele.     

Effect of menstrual cycle and hormonal treatment on ki-67 and bcl-2 expression and adenomyosis.

OBJECTIVE: To study the expression of proliferation markers (ki-67) and anti-apoptotic protein (bcl-2) in adenomyotic lesions during the menstrual cycle or following the use of steroid hormones. PATIENTS AND METHODS: Ninety patients of reproductive age were included, who were submitted to endometrial resection for treatment of adenomyosis-related menorrhagia. Seven patients were using oral contraceptives and another seven had a levonorgestrel intrauterine device (IUD) (Mirena) in the uterine cavity at the time of the hysteroscopic procedure. Untreated patients were divided into four groups: menstruation/early proliferative phase (n = 24), late proliferative (n = 19), early luteal phase (n = 7) and late luteal phase (n?=?26). Bcl-2 and ki-67 expression was determined in paraffin-embedded tissue blocks using immunohistochemical methods. RESULTS: Proliferation rates in adenomyotic lesions increased during the proliferative phase, reaching a peak during ovulation to decrease to values close to zero in the late luteal phase. Bcl-2 expression showed a similar curve with peak values during the later proliferative phase followed by a significant decrease in the number of cases showing strong positive expression in the late luteal phase. Both Mirena and oral contraceptives decreased ki-67 expression on adenomyosis but only Mirena was affective in diminishing bcl-2 expression. CONCLUSION: During the luteal phase, both ki-67 and bcl-2 expression is reduced in adenomyotic lesions in a similar way to that occurring in patients using Mirena. Oral contraceptives, on the other hand, do not affect bcl-2 expression in adenomyosis.     

Effects of the route of estrogen administration and exercise on hormonal levels in postmenopausal women

Objective: To examine the effects of exercise on serum estrogens, growth hormone, insulin, cortisol, lactate, and glucose levels in postmenopausal women receiving two routes of administration of estrogen replacement therapy (ERT).

Design: Prospective, randomized, crossover study.

Setting: The general clinical research center of an academic medical center.

Patient(s): Eleven active, postmenopausal women.

Intervention(s): The patients were screened with exercise stress testing, then oral micronized estradiol or transdermal estradiol was administered, followed by two 45-minute submaximal exercise tests. Dietary intake before the tests was standardized.

Main Outcome Measure(s): The study measured maximal heart rate and aerobic power ( ₂max), and serum levels of estradiol (E₂), estrone (E₁), cortisol, growth hormone (GH), insulin, glucose, and lactate.

Result(s): Growth hormone, cortisol, and insulin all changed significantly in response to the 45-minute exercise bouts, but no differences were observed between the oral micronized estradiol and transdermal estradiol responses. E₂ levels increased significantly during the transdermal estradiol 45-minute exercise bout; this change did not occur during the oral estradiol exercise bout. In the transdermal estradiol treatment group, the E₂ levels at +30 and +45 minutes of exercise were elevated compared to the post-exercise levels at −15, 0, and 30 minutes. E₁ was not significantly changed during the 45-minute exercise bouts in either group.

Conclusion(s): During exercise, serum E₂ levels rise significantly higher with transdermal but not oral routes of E₂ administration. However, the elevated levels are not prolonged and normalize by 30 minutes after exercise.