Constant estrogen, intermittent progestogen vs. continuous combined hormone replacement therapy: tolerability and effect on vasomotor symptoms.

OBJECTIVE: To compare the efficacy and tolerability of a novel oral constant estrogen plus intermittent progestogen hormone replacement therapy (HRT) regimen to a continuous combined HRT regimen in postmenopausal women. METHODS: Subjects were randomly assigned to receive treatment with either constant 17beta-estradiol (E2), 1 mg, plus intermittent norgestimate (NGM) 90 microg (3 days off, 3 days on) (n=221) or E2 2 mg/norethisterone acetate (NETA) 1 mg (n=217) for 1 year. Treatments were evaluated based on the incidence of hot flushes and uterine bleeding. RESULTS: Both regimens had similar bleeding profiles and provided comparable vasomotor symptom relief. However, breast discomfort and edema were experienced by twice as many subjects who received E2/NETA. CONCLUSIONS: The constant E2/intermittent NGM regimen was well tolerated and possesses similar efficacy compared with a continuous combined E2/NETA regimen and may be considered whenever HRT without withdrawal bleeding is deemed appropriate.

Effects on serum lipid profiles of continuous 17beta-estradiol, intermittent norgestimate regimens versus continuous combined 17beta-estradiol/norethisterone acetate hormone replacement therapy.

OBJECTIVE: To compare the effects of a daily oral 1-mg dose of continuous 17beta-estradiol (E2) plus intermittent (3 days off, 3 days on) norgestimate (NGM) 90 microg (n = 221), an oral 2-mg dose of continuous E2 plus intermittent NGM 180 microg (n = 219), and an oral 2-mg dose of continuous E2 plus continuous norethisterone acetate (NETA) 1 mg (n = 217) on blood lipids and lipoproteins in postmenopausal women. BACKGROUND: The present study was undertaken because some progestins have adverse effects on lipid profiles, thereby negating the favorable effects of estrogens. METHODS: This was a multicenter, randomized, parallel-group trial that focused primarily on the 2 marketed regimens--E2 1 mg/NGM 90 microg and E2/NETA. Both subjects and investigators were blinded to the intermittent regimens; the continuous combined regimen was administered open-label. After a minimum 12-hour overnight fast, blood samples were collected at baseline and during months 7 and 12 to determine lipid and lipoprotein concentrations using validated methods. RESULTS: E2 1 mg/NGM 90 microg was associated with significant (ie, the 95% CI did not include 0) increases in high-density lipoprotein cholesterol (HDL-C) (6.8% [95% CI = 4.7%, 9.0%] and 4.8% [2.3%, 7.2%] at months 7 and 12, respectively) and high-density lipoprotein 2 cholesterol (HDL2-C) (10.8% [6.2%, 15.3%] and 24.1% [18.9%, 29.4%]) concentrations, and decreases in total cholesterol (-7.7% [-9.0%, -6.3%] and -9.2% [-10.5%, -7.9%]), low-density lipoprotein cholesterol (-14.3% [-16.3%, -12.4%] and -14.9% [-16.7%, -13.2%]), and lipoprotein(a) (-30.6% [-41.4%, -20.0%] at month 12) concentrations. A significant difference (P < 0.001 by analysis of variance) between the E2 1-mg/NGM 90-microg and NETA regimens was seen for HDL-C and HDL2-C concentrations, which were elevated in subjects receiving E2 1 mg/NGM 90 microg but reduced (-9.1% [-11.1%, -7.1%] and -12.3% [-14.3%, -10.3%] for HDL-C at months 7 and 12, respectively; -14.2% [-18.0%, -10.4%] and -2.5% [-7.8%, +2.8%] for HDL2-C at months 7 and 12, respectively) in those receiving E2/NETA. CONCLUSIONS: In the present study, continuous E2 1 mg/NGM 90 microg was associated with beneficial effects on lipids and lipoproteins in healthy postmenopausal women, effects that were greater at least for HDL-C and HDL2-C than those observed with continuous combined E2/NETA. The applicability of the study results to women with preexisting cardiovascular disease or dyslipidemia, or those who are overweight, remains to be investigated.

Effects of maternal dexamethasone administration on fetal Doppler flow velocity waveforms.

OBJECTIVE: To investigate the effects of maternal dexamethasone administration on umbilical and fetal cerebral artery flow velocity waveforms. DESIGN: Cross-sectional study. SETTING: Department of Obstetrics and Gynaecology, Robert Ballanger Hospital, Aulnay-sous-Bois, France. SAMPLE: Twenty-six pregnant women with singleton pregnancies considered at risk for preterm delivery. At baseline, all pregnancies had normal fetoplacental vascular resistance. METHODS: These women were given weekly six intravenous doses of 4 mg of dexamethasone eight hours apart. MAIN OUTCOME MEASURES: Doppler studies were performed from both umbilical artery (UA) and fetal middle cerebral artery (MCA) before (day 0), during (day 2), immediately after (day 4) and shortly after (day 7) every steroid course. RESULTS: No significant variation was noted in both umbilical artery pulsatility index (PI) and fetal heart rate through dexamethasone therapy. Compared with mean initial values, we found on day 4 a significant decrease in MCA PI of 0.28 (F = 7.17, P < 0.001) and a significant increase in UA:MCA PI ratio of 0.08 (F = 3.85, P = 0.013); in contrast no significant change was documented on days 2 and 7 in both MCA pulsatility index and UA:MCA PI ratio. After multiple regression analysis, only the decrease in fetal middle cerebral artery pulsatility index on day 4 remained significant (F= 5.84, P= 0.001). CONCLUSIONS: The current study finds in healthy fetuses a transient, significant and unexplained decrease in fetal middle cerebral artery impedance on the fourth day following maternal dexamethasone administration. Further basic research and clinical studies including larger sample sizes or pregnancies with fetoplacental dysfunction are needed.

Absence of flow velocity waveform changes in uterine arteries after bilateral internal iliac artery ligation.

A case is reported of bilateral internal iliac artery ligation during cesarean delivery for intractable hemorrhage. Uterine artery Doppler flow velocity waveforms were documented before and after the procedure. After the ligation the uterine arteries could still be visualized in the appropriate anatomic location, and no changes in Doppler flow velocity waveforms were documented.

A novel intermittent regimen of norgestimate to preserve the beneficial effects of 17beta-estradiol on lipid and lipoprotein profiles.

OBJECTIVE: This study was undertaken to evaluate the effects of 3 dosage levels of intermittent norgestimate plus a constant dose of 17beta-estradiol on blood lipid and lipoprotein concentrations in 236 postmenopausal women. STUDY DESIGN: In this multicenter, double-blind, parallel-group trial the subjects were randomly assigned to receive 1 mg estradiol daily or 1 mg estradiol daily plus intermittent (3 days off and 3 days on) doses of 30 microg, 90 microg, or 180 microg norgestimate for 360 days. RESULTS: The regimens of 1 mg estradiol plus 30 microg norgestimate and 1 mg estradiol plus 90 microg norgestimate increased concentrations of high-density lipoprotein cholesterol, HDL(2) high-density lipoprotein cholesterol, HDL(3) high-density lipoprotein cholesterol (except the regimen of 1 mg estradiol plus 30 microg norgestimate at 7 months), and apolipoprotein apo A-I. They decreased total cholesterol concentration, low-density lipoprotein cholesterol concentration, low-density lipoprotein/high-density lipoprotein ratio, apolipoprotein apo B concentration, and Lp(a) lipoprotein concentration, and they attenuated estradiol-induced increases in triglyceride concentrations. In contrast, the regimen of 1 mg estradiol plus 180 microg norgestimate reduced concentrations of high-density lipoprotein cholesterol, high-density lipoprotein HDL(3) cholesterol, and apolipoprotein apo A-I at 7 months and increased the low-density lipoprotein/high-density lipoprotein ratio at 7 months. CONCLUSIONS: An intermittent regimen of norgestimate at 30 or 90 microg daily administered for 3 days off followed by 3 days on preserved the beneficial lipid and lipoprotein changes induced by continuous therapy with 1 mg 17beta-estradiol daily; however, 180 microg norgestimate did not do so.

Effect of a unique constant-estrogen, pulsed-progestin hormone replacement therapy containing 17beta-estradiol and norgestimate on endometrial histology.

OBJECTIVE: To evaluate the effect of a 17beta-estradiol(E2)/norgestimate (NGM) HRT regimen, which provides constant estrogen in combination with pulsed progestin administration, on endometrial histology in healthy postmenopausal women 40 to 65 years of age who had experienced natural menopause at least 12 months before the start of the study. METHODS: A total of 1,253 postmenopausal women were randomized to receive either continuous 1 mg E2, or constant estrogen, pulsed progestin regimens of 1 mg E2/30 microg NGM, 1 mg E2/90 microg NGM, or 1 mg E2/180 microg NGM (3 days on, 3 days off) in a 12-month, multicenter, double-blind study. Endometrial biopsies were obtained pre- and post-treatment, and were evaluated by at least 2 (if required, by 3) pathologists who were blinded with respect to treatment and to each other's diagnosis. RESULTS: At the end of the study, no cases of endometrial hyperplasia were diagnosed in subjects who received E2 1 mg/NGM 90 microg or E21 mg/NGM 180 microg, whereas 74 (28%) and 16 (6%) cases of endometrial hyperplasia were diagnosed in subjects who received continuous E2 1 mg and E2 1 mg/NGM 30 microg, respectively. A dose-related endometrial response to NGM was apparent (P < .001). The percentage of patients with inactive/atrophic endometrium increased with NGM dose. CONCLUSION: The results of this study support the safety and efficacy of this unique HRT regimen and suggest that the minimal NGM dose required to protect the endometrium from hyperplasia in a pulsed progestin regimen consisting of continuous E2 1 mg is 90 microg.

Efficacy and safety of a constant-estrogen, pulsed-progestin regimen in hormone replacement therapy.

OBJECTIVE: Two studies (Studies A and B) were conducted to measure efficacy and safety of constant 17beta-estradiol (E2), pulsed norgestimate (NGM) hormone replacement therapy on bleeding and vasomotor symptoms in postmenopausal women. NGM was pulsed in a 3-days-off/3-days-on fashion. Study A also assessed effects of treatment on vaginal cytology. STUDY DESIGN: In two 360-day, multicenter, double-blind, parallel-group studies, 1,253 subjects were randomized to receive daily, unopposed E2 1 mg or one of three constant estrogen, pulsed progestin regimens: E2 1 mg/NGM 30 microg, E2 1 mg/NGM 90 microg, or E2 1 mg/NGM 180 microg. RESULTS: Bleeding control improved over time in women treated with E2 1 mg/NGM 90 microg: 69% of women were free of bleeding (irrespective of spotting) during month 1, 71% during month 6, and 80% during month 12. E2 1 mg/NGM 30 microg had a lower incidence of bleeding but provided inadequate endometrial protection. Among subjects with vasomotor symptoms at baseline, the percentage of asymptomatic subjects at the end of 3 months was 70% in the E2 1-mg group and 76% in the E2 1-mg/NGM 90-microg group. E2 1 mg/NGM 90 microg was at least as effective as E2 1 mg alone in causing maturation of vaginal epithelial cells. All regimens were well tolerated. CONCLUSION: Pulsed dosing of NGM 90 microg for 3 days off and 3 days on along with continuous administration of E2 is effective in treating vasomotor symptoms and vulvovaginal atrophy, provides endometrial protection (i.e., no cases of endometrial hyperplasia or cancer), and has a bleeding profile acceptable to the majority of women studied.

Detection and measurement of fetomaternal hemorrhage following diagnostic cordocentesis.

OBJECTIVE: The aim of this study was to investigate the effect of cordocentesis on fetomaternal hemorrhage (FMH). METHODS: One hundred and three diagnostic cordocenteses, without any other associated procedure, were performed at 23-40 weeks' gestation. FMH was detected using the Kleihauer-Betke staining of maternal blood taken immediately before and after cordocentesis. RESULTS: Significant FMH occurred after 40 (38.8%) of the 103 procedures. An increased risk of fetal bleeding was associated with both an anterior placenta (odds ratio (OR) 5.89; 95% confidence interval (CI) 2.27-15.3; p < 0. 001) and a transplacental cordocentesis (OR 37.0; 95% CI 2.15-636; p < 0.001). The volume of FMH was greater after cordocentesis with an anterior placenta (90th percentile 6.20 ml) than after cordocentesis with a lateral (90th percentile 4.58 ml) or posterior placenta (90th percentile 1.35 ml) (p < 0.001). After fetal blood sampling, significant FMH occurred more frequently with a procedure duration of 3 min or more (OR 4.45; 95% CI 1.70-11.7; p = 0.002) and with two or more needle insertions (OR 4.65; 95% CI 1.80-12.1; p = 0.001). CONCLUSION: FMH following cordocentesis may be related to placental injuries. This event is influenced by placental location, procedure duration and the number of needle insertions.

Changes in umbilical artery, middle cerebral artery, and aorta blood flow Doppler waveform pulsatility indices after funisocentesis.

This study evaluates the effect of funisocentesis on umbilical artery, fetal cerebral artery, and aortic circulation. The pulsatility index in the umbilical artery, fetal middle cerebral artery, and descending aorta was measured by pulsed Doppler ultrasonography before and after 41 diagnostic funisocenteses. Percutaneous umbilical artery blood sampling was associated with a significant decrease in umbilical artery pulsatility index (mean -0.132, standard deviation 0.259, P = 0.002) and in middle cerebral artery pulsatility index (mean -0.143, standard deviation 0.260, P = 0.001). The decline in resistance to flow of the umbilical artery (r = 0.340, P = 0.029) and middle cerebral artery (r = 0.457, P = 0.002) was correlated with gestational age at sampling. These findings suggest that alterations in the waveforms from both the umbilical and the fetal cerebral circulations can be induced by fetal blood sampling.

[Predictive value of cervical-vaginal prolactin in the evaluation of premature labor risk]. / Valeur prédictive de la prolactine cervico-vaginale dans l'évaluation du risque d'accouchement prématuré.

OBJECTIVES: To determine whether the presence of cervico-vaginal prolactin during pregnancy is significantly associated with preterm delivery. STUDY DESIGN: A cohort of 64 pregnant women between 21 and 34 weeks of amenorrhea underwent a washing of the exocervix and vaginal fornices with a normal saline solution. The fluid was then aspirated and centrifuged. Samples were stored at -70 degrees C and later prolactin level was determined by radioimmunoassay. Test was considered as positive for a prolactin concentration higher than 2 ng/ml. Statistical analysis were realized by Student's t test, Fisher's exact test and chi 2 test. RESULTS: In patients with preterm labor, positive cervico-vaginal prolactin had a positive predictive value of 36% and a negative predictive value of 94% for a preterm delivery before 34 weeks of gestation (respectively 45% and 79% before 37 weeks). The sensitivity of a positive test was 31% for preterm delivery before 37 weeks of gestation and specificity was 87% (respectively 57% and 88% before 34 weeks). Patients with a positive prolactin test had a significantly shorter latency between testing and delivery (33.7 days vs 52.4 days; p < 10(-9)). No delivery occurred during the following weeks for patients with a negative prolactin test and, among those, only one delivery occurred during the second week following the test. Positive prolactin tests correlated with a mean cervical dilatation of 1 centimetre at the time of testing, while it was of 0.6 centimetre for patients with a negative prolactin test. CONCLUSIONS: Cervico-vaginal prolactin seems to be a non convincing marker for preterm delivery but indicative of a shorter latency from testing to delivery in symptomatic patients. Further investigations are necessary to evaluate accuracy of cervico-vaginal prolactin as a biochemical marker for imminent delivery in patients with preterm labor.

Ominous normalization of middle cerebral artery flow velocity waveforms preceding fetal death: case report.

The loss of middle cerebral artery compensatory vasodilation appears to be ominous in fetuses with absent end-diastolic umbilical waveforms. The authors report a case with a loss of the 'brain-sparing effect' 24 h before fetal death. Current pathophysiological explanations are discussed.

[Doppler velocimetry in the umbilical, middle cerebral and aortic arteries, before and after cordocentesis]. / Vélocimétries Doppler des artères ombilicales, cérébrales moyennes et aortiques, avant et après cordocentèse.

OBJECTIVE: Prospectively evaluate the effect of cordocentesis on the umbilical, fetal cerebral and aortic circulation. METHOD: Fetal blood was sampled for diagnostic purposes in 21 pregnant women at 21 to 38 weeks gestation. Ten patients undergoing amniocentesis served as controls. The resistance index (RI) in the umbilical and middle cerebral arteries and the mean blood velocity (Vm) in the descending aorta were measured with pulsed Doppler before and after blood sampling. Variations in umbilical and cerebral RI and in aortic Vm were recorded. RESULTS: There was a significant drop in both umbilical RI (mean +/- SD = -0.049 +/- 0.078; p = 0.009) and middle cerebral RI (-0.077 +/- 0.058; p < 0.0001) after cordocentesis. The drop in umbilical RI was greater when the second Doppler measurement was made early, when the blood was sampled transplacentally and in early gestational age. Reduction in fetal cerebral artery RI was also greater for transplacental puncture. The fetal descending aorta Vm did not change significantly after blood sampling. There were no variations in Doppler index before and after amniocentesis. CONCLUSIONS: Changes in blood flow velocity waveforms as measured by pulsed Doppler in the umbilical and fetal cerebral arteries can be induced by fetal blood sampling. Decreased resistance in the placenta and fetal circulation would imply release of nitric oxide.

[Congenital auriculo-ventricular block and anti-Ro (SS-A)/anti-La (SS-B) antibody]. / Bloc auriculo-ventriculaire congénital et anticorps anti-Ro (SS-A)/anti-La (SS-B).

Congenital heart blocks due to immunological causes are rare. A case is reported of a fetus with auriculo-ventricular block diagnosed at 22 weeks of amenorrhoea and intrauterine death at 32 weeks. The authors discussing the case find the most likely link: an anti-RO (SS-A) and anti-LA (SS-B) immunological block and they suggest that there are minor localised lesions in the nodal tissue which gives rise to benign disturbances of cardiac rhythm and they point out ways of preventing intrauterine auriculo-ventricular block.

[Possibilities and limitations of the acetic acid test in the identification of vulvar papillomavirus lesions. A colposcopic, histologic and virologic study]. / Apports et limites du test à l'acide acétique dans l'identification des lésions vulvaires à papillomavirus. Etude colposcopique, histologique et virologique.

42 subclinical HPV related vulvar lesions have been studied by Southern Blot Hybridization and histological samplings. 15 women had normal Pap smears. Cervical intraepithelial neoplasia was present in 24 other women, 15 of them had HPV on Southern Blots. Macular or papular areas on the vulva were strongly correlated with HPV infection, since 6 out 9 of them harboured HPV 16, 42 or X. Histologically, flat condyloma was present in 6 cases. However, 33 nonspecific acetowhite reactions of the vulva were free of HPV. It is therefore important to recognize such aspects on colposcopical examination of the vulva to avoid unnecessary treatment.

[Cancer of the endometrium: epidemiology, histology, diagnostic methods]. / Cancer de l'endomètre: épidémiologie, histologie, moyens diagnostiques.

Endometrial cancer has become one of the most frequent female cancers, second only to breast cancer. It must be looked for in women presenting several high risk factors for endometrial cancer, the common denominator of which is absolute or relative hyperoestrogenism. Hysteroscopy and guided biopsy are the most reliable techniques for the diagnosis of endometrial cancer and its precursors. These techniques must be used in symptomatic patients and in asymptomatic but high risk women whose selection remains controverted as regards the mass detection method.

[Subclinical vulvar lesions. Vulvoscopic and histologic aspects. Apropos fo 74 cases]. / Lésions infracliniques vulvaires. Aspects vulvoscopiques et histologiques. A propos de 74 cas.

Subclinical vulvar lesions have been studied using the magnifying colposcope after 5% acetic acid application in 65 women with H.P.V. related cervical lesions and/or cervical intraepithelial neoplasms. Different vulvoscopic patterns are described: micropapillae (51%), diffuse acetowhite reaction (18%), papules (13%) and leukoplakia (11%). A normal appearance was found in 7% of the cases. Histological diagnosis is far different: normal histological appearance or minimal histological changes are noted in 57% of the biopsy specimens, flat condylomas of the vulva in 38% and vulvar intraepithelial neoplasms (V.I.N.) in 15%. The most frequent clinical aspects, i.e., acetowhite reaction and micropapillae are seldom related to V.I.N. The significance of these H.P.V. histologically-related vulvar lesions is still difficult to assess. Unlike cervical intraepithelial neoplasms, the malignant potential of V.I.N. remains uncertain. The risk of progression to invasive cancer in young women is low, probably less than 5%. On the other hand, vulvae may harbour H.P.V. able to influence subsequent recurrences of dysplasias of the cervix. Further studies are needed, especially Southern blot hybridization of vulvar biopsy specimens, to determine whether these histological abnormalities definitely harbour viruses and need subsequent treatment.