Serum luteinizing hormone concentrations increase 100-fold in females from 7 years to adulthood, as measured by time-resolved immunofluorometric assay.

The increases in serum immunoreactive (RIA) LH and FSH concentrations during puberty are small and of limited value in the evaluation of pubertal development. We, therefore, used highly sensitive time-resolved immunofluorometric assays to evaluate the changes in LH and FSH during female puberty. The sensitivity of the LH assay was 0.02 IU/L, and that of the FSH assay was 0.01 IU/L. Fifty normal premenarcheal girls, 7-12 yr old, 15 postmenarcheal girls, 16 to 17 yr old, and 15 adult women, 24-29 yr old, were studied. In postmenarcheal women, the blood samples were taken on cycle days 4-7. Serum estradiol concentrations were measured by RIA, and pubertal stages were graded. Serum LH levels in prepubertal girls were very low; the mean concentration was 0.05 IU/L. All girls less than 10 yr of age had serum LH concentrations below 0.2 IU/L, while FSH levels varied from 0.3-2.0 IU/L. The earliest significant changes in serum LH, FSH, and estradiol levels took place simultaneously at 9-10 yr of age. The increase in serum FSH was gradual, but the increase in serum LH was sudden and very steep, coinciding with the increase in serum estradiol and the onset of physical puberty. The increase in the mean LH concentrations between the 7-yr-old and the adult group was 116-fold, that for estradiol was 12-fold, and that for FSH was 6.7-fold. These results suggest that the increase in serum LH is important at the onset of puberty, and LH concentrations are a sensitive indicator of pubertal development.

Short-term metabolic effects of isradipine and metoprolol in pre-eclampsia.

OBJECTIVE: To study the effects of isradipine or metoprolol on insulin sensitivity and lipid profiles as well as on blood pressure and umbilical vascular resistance in pre-eclamptic women in the third trimester of pregnancy. DESIGN: A single-centre, prospective, randomized, double-blind, double-dummy and parallel-group study. SETTING: Helsinki University Central Hospital, a tertiary referral centre. PATIENTS: Twenty-four previously healthy pregnant women with normal findings in an oral glucose-tolerance test who were hospitalized for preeclampsia, of whom 17 completed the study. INTERVENTIONS: Between 29 and 39 weeks of gestation, measurements were made of insulin sensitivity (the minimal model), magnitude of proteinuria, and the fasting levels of serum uric acid, lipids and lipoproteins. Subsequently, treatment with isradipine 2.5 mg (n = 9) or metoprolol 50 mg (n = 8) twice daily was started, and these women were reinvestigated 5-7 days later. Blood pressure was recorded during 24 h by automated ambulatory blood pressure measurement. Umbilical artery resistance index was measured by Doppler ultrasound. MAIN OUTCOME MEASURES: Insulin sensitivity, uric acid, degree of proteinuria, lipids and lipoproteins, blood pressure, umbilical artery resistance index. sensitivity, degree of proteinuria, blood pressure, or the umbilical artery resistance index. Serum uric acid increased in both groups (P<0.05). High-density lipoprotein2 cholesterol increased 15.6% in the isradipine group (P<0.05), but no significant changes appeared in other lipids and lipoproteins in either group. CONCLUSIONS: In this study, short-term antihypertensive treatment with isradipine or metoprolol in preeclampsia had no detrimental effect on serum lipid and lipoprotein levels or insulin sensitivity.

Conservative treatment of ectopic pregnancy.

As a conservative nonsurgical treatment of an early ectopic pregnancy, local prostaglandin, parenteral or local methotrexate, local hyperosmolar glucose, and also expectant management have been used successfully in selected cases. The success rate of conservative treatment has been 71%-100% and that of tubal patency after different kinds of conservative treatment 72-93% of patients. In the present study of expectant management in early ectopic pregnancy in patients with decreasing serum hCG levels, spontaneous resolution was observed in 64.6% of patients and in the total series of 207 ectopic pregnancies in 15.0% of patients. Expectant management of early ectopic pregnancy is recommended when emergency surgery is not needed on admission and the serum hCG level is decreasing as noted in two consecutive estimations with an interval of 1-2 days.

Comparison of abdominal and vaginal sonography in suspected ectopic pregnancy.

We compared the accuracy of vaginal sonography in 100 women suspected of having an ectopic pregnancy, in whom a living fetus was not seen by abdominal sonography. Vaginal sonography provided more useful diagnostic information in 44% of the cases, 31% of the ectopics and 52% of the intrauterine pregnancies. Among the 39 ectopic gestations, vaginal scanning was more accurate than abdominal scanning in detecting the ectopic pregnancy (90 versus 80%) and cul-de-sac fluid (77 versus 46%), in identifying an ectopic gestational sac (69 versus 44%), and in diagnosing a tubal pregnancy as unruptured (76 versus 50%). Only one false-positive diagnosis was made by each method of scanning. Among the 61 intrauterine pregnancies, vaginal scanning allowed a more accurate detection of the content of the sac (fetus/yolk sac) in 49% of the cases. In two women, normal intrauterine sacs of 2 and 2.5 mm were detected only by vaginal scanning, at hCG levels of 740 and 840 IU/L (First International Reference Preparation), respectively. Vaginal scanning appears important for early diagnosis of intrauterine pregnancy and more accurate diagnosis of ectopic pregnancy.

Transvaginal sonographic findings in ambulatory patients with suspected pelvic inflammatory disease.

OBJECTIVE: To evaluate transvaginal sonographic findings in ambulatory patients with suspected pelvic inflammatory disease (PID). METHODS: We studied 51 outpatients with a mean age of 26.8 years (range 16-52) who had a history of low abdominal pain, negative pregnancy test, and no gynecologic procedures performed during the last month. Endometrial biopsy was used for the histopathologic diagnosis. The presence of plasma cell endometritis was used as the criterion standard for the diagnosis of PID. Sonography was performed before biopsy in a blinded fashion without knowledge of the clinical findings and laboratory results except for the pregnancy test. Repeat pelvic and ultrasound examinations were performed 4 weeks after antimicrobial therapy. RESULTS: Endometrial biopsy revealed plasma cell endometritis in 13 cases (25%). Thickened fluid-filled tubes were seen in 11 of 13 patients (85%) with plasma cell endometritis and in none of those without. Other sonographic findings associated with plasma cell endometritis were polycystic-like ovaries and free pelvic fluid. A sonogram suggestive of PID, ie, thickened fluid-filled tube with or without free pelvic fluid, had a sensitivity of 85% and a specificity of 100% for the diagnosis of plasma cell endometritis. None of the patients with a normal sonogram or simple cyst had plasma cell endometritis. Repeat examination after 4 weeks showed that the sonographic findings had resolved in 60% of the patients who had had histologic evidence of infection. CONCLUSION: Transvaginal sonography can facilitate the outpatient management of patients with suspected PID.

Randomized comparison of oral and transdermal hormone replacement on carotid and uterine artery resistance to blood flow.

OBJECTIVE: To compare the long-term effects of oral and transdermal hormone replacement therapy (HRT) on carotid and uterine vascular impedance. METHODS: Sixty-three postmenopausal women were randomized to 1 year's treatment with oral or transdermal sequential combined HRT. Carotid and uterine artery pulsatility indices (PIs) were assessed by color Doppler at baseline, and after 2, 6, and 12 months of treatment. Fifty-eight women completed the trial, 27 in the oral and 31 in the transdermal group. In a subgroup of 30 women, we also performed Doppler measurements in the estrogen-progestin combined phase. The study had 90% power to detect a difference between treatment groups of 0.05 in the carotid artery and of 0.25 in uterine artery PI at the 5% significance level. RESULTS: The carotid PI decreased significantly (P < .001) and similarly during both regimens. This drop was already clearly detectable during the second month, from 0.97 (0.95, 1.01) (mean and 95% confidence intervals [CII) to 0.94 (0.91, 0.97) in the oral and from 0.98 (0.94, 1.00) to 0.92 (0.89, 0.95) in the transdermal group, but it continued up to 12 months (0.85 [0.82, 0.88], 13% of baseline values in the oral group and 0.84 [0.81, 0.871, 14% in the transdermal group). In the uterine arteries, the drop in PI was steeper and greater and reached its maximum at 6 months (39% and 40%, respectively). Drops in carotid and uterine PI correlated positively with baseline PI values, but were not affected by patient age, time from menopause, previous HRT and smoking. Addition of norethisterone acetate did not counteract drops in carotid and uterine PI in either group. CONCLUSION: Oral and transdermal sequential HRT are similarly effective at 1 year in reducing impedance to flow in carotid and uterine circulation. This long-term vascular effect might explain how HRT protects women from cardiovascular disease.

Expectant management of ectopic pregnancy.

OBJECTIVE: To evaluate expectant management in selected cases of ectopic pregnancy. METHODS: Transvaginal sonography and estimation of serum hCG concentrations were used in the evaluation and follow-up of ectopic pregnancy. Entry criteria for expectant management were: decreasing level of serum hCG, diameter of the ectopic pregnancy less than 4 cm, and no signs of rupture or acute bleeding by vaginal sonography. RESULTS: Expectant management was studied in 83 patients, representing 26% of all ectopic pregnancies during a 2-year period. In 57 patients (69%), spontaneous resolution occurred, corresponding to 18% of all ectopic pregnancies. Laparoscopy was performed in 26 because of clinical symptoms or a rise in hCG level after expectant management for 1-18 days. One patient had a tubal rupture requiring tubal resection by laparoscopy. No serious complications occurred. With increasing experience, the rate of expectant management and spontaneous resolution increased during study period. CONCLUSION: Expectant management with repeated vaginal sonography and estimations of serum hCG concentrations is a useful form of treatment for ectopic pregnancy in selected cases.

Vaginal clindamycin in preventing preterm birth and peripartal infections in asymptomatic women with bacterial vaginosis: a randomized, controlled trial.

OBJECTIVE: To determine whether treatment of bacterial vaginosis (BV) in early pregnancy decreases the risk of preterm delivery and peripartum infectious morbidity. METHODS: In this multicenter, randomized, double-masked, placebo-controlled intervention trial, screening for BV was performed by vaginal Gram stain obtained from 5432 healthy women with singleton pregnancies during the first antenatal clinic visit at 10--17 weeks' gestation. Bacterial vaginosis-positive women with no past history of preterm delivery were randomized to a single course of treatment with either 2% vaginal clindamycin cream or identical placebo cream for 7 days. Repeat Gram stains were taken 1 week after treatment and at 30--36 weeks' gestation. Preterm delivery was defined as spontaneous delivery before 37 gestational weeks. Peripartum infectious morbidity was defined as postpartum endometritis, postpartum sepsis, postcesarean wound infection, or episiotomy wound infection, necessitating antimicrobial therapy. According to the power analysis, 180 patients were needed for both treatment arms to show a three-fold difference in the rates of preterm births. RESULTS: The overall prevalence of BV was 10.4%. Of all BV-positive women, 375 (66%) were randomized to the treatment arms. The primary cure rate was 66% in the clindamycin group; in the placebo group, 34% spontaneously cleared BV (odds ratio [OR] 1.9, 95% confidence interval [CI] 1.3, 2.8). The rate of preterm deliveries was 5% in the clindamycin group and 4% in the placebo group (OR 1.3, 95% CI 0.5, 3.5). The rate of peripartum infectious morbidity was 11% in the clindamycin group and 18% in the placebo group (OR 1.6, 95% CI 0.9, 2.8). Bacterial vaginosis recurred in 7% of women. The rate of preterm deliveries was 15% in this subgroup compared with 2% among women who remained BV negative (OR 9.3, 95% CI 1.6, 53.5). CONCLUSION: Vaginal clindamycin did not decrease the rate of preterm deliveries or peripartum infections, but recurrent or persistent BV increased the risk for these complications.

Evidence of interplay between plasma endothelin-1 and 17 beta-estradiol in regulation of uterine blood flow and endometrial growth in infertile women.

OBJECTIVE: To determine the effects of gonadotropin-induced ovarian stimulation on the plasma levels of endothelin-1 as well as on uterine blood flow and endometrial thickness. DESIGN: Controlled cross-over clinical study. SETTING: Academic research environment. PATIENT(S): Eighteen volunteer infertile women (31.4 +/- 2.5 years, mean +/- SE) participating in an IVF-ET program. INTERVENTION(S): Transvaginal Doppler ultrasound was performed and blood samples were collected 4 days after the LH surge in a spontaneous cycle and 4 days after hCG administration in a subsequent gonadotropin-stimulated cycle. MAIN OUTCOME MEASURE(S): Plasma levels of E2, P, and endothelin-1; uterine artery pulsatility index; and endometrial thickness. RESULT(S): Stimulated cycles were associated with significantly higher E2 levels (101.0 +/- 10.2 versus 723.5 +/- 57.3 pg/mL [conversion Factor to SI unit, 3.671]; spontaneous versus stimulated), thicker endometrium (9.2 +/- 2.5 versus 11.4 +/- 2.9 mm), and lower endothelin-1 levels (2.5 +/- 0.1 versus 2.1 +/- 0.1 pg/mL [conversion factor to SI unit, 0.4]) and pulsatility index (3.22 +/- 0.12 versus 2.63 +/- 0.08) than spontaneous cycles. Endothelin-1 correlated negatively with E2 (r = -0.38), but not with P or pulsatility index. Differences in endothelin-1 and endometrial thickness between spontaneous and stimulated cycles correlated negatively (r = -0.56) with each other. CONCLUSION: Our results suggest an inhibitory role for E2 in the release of endothelin-1, which could be a factor in the regulation of uterine and endometrial blood flow.

Transvaginal Doppler study of uterine artery blood flow in in vitro fertilization-embryo transfer cycles.

OBJECTIVE: To verify whether uterine artery impedance, measured as pulsatility index and resistance index is related to the outcome of in IVF-ET cycles. DESIGN: Prospective study of infertile women participating in an IVF-ET program. SETTING: University Hospital. PATIENTS: Two hundred women (24 to 40 years of age), who had one to three good quality embryos transferred to the uterus after a standardized IVF cycle. INTERVENTION: Transvaginal color Doppler and a blood sample on the day of ET. MAIN OUTCOME MEASURES: Uterine artery pulsatility index and resistance index, endometrial thickness, serum E2 and P concentrations, clinical pregnancy rate (PR). RESULTS: Pulsatility indices and resistance indices were lower in conception (2.45 +/- 0.54 and 0.85 +/- 0.04, respectively) than in nonconception cycles (2.66 +/- 0.39 and 0.87 +/- 0.04, respectively), although the overlap of the values is considerable. Overall PR was 35% per ET, and it decreased significantly when pulsatility index was > 3.0 (15%) and resistance index > 0.92 (13%), being lowest when pulsatility index was > 3.3 and resistance index > 0.95 (10%). Such a high impedance was detected in 9% of nonconception cycles. CONCLUSION: In IVF-ET cycles the uterus is likely to be unreceptive when uterine artery pulsatility index is > 3.3 and resistance index > 0.95 before ET, but this occurs only in 9% of the cycles.

The long-term effects of oral and transdermal postmenopausal hormone replacement therapy on nitric oxide, endothelin-1, prostacyclin, and thromboxane.

OBJECTIVE: Oral postmenopausal hormone replacement therapy (HRT) decreases the risk of cardiovascular disorders, but the mechanisms of this protection are largely unknown. We compared the long-term effects of sequential oral HRT and transdermal HRT on vasodilatory nitric oxide and prostacyclin as well as vasoconstrictive endothelin- and thromboxane A2, all of which may be factors in the protective effect of HRT against cardiovascular disorders. DESIGN: Prospective, randomized study. SETTING: Department of Obstetrics and Gynecology at a university hospital. PATIENT(S): Fifty-two healthy postmenopausal female nonsmokers (n = 42) or smokers (n = 10) who had climacteric symptoms. INTERVENTION(S): The women received either oral HRT (2 mg of estradiol on days 1-12, 2 mg of estradiol plus 1 mg of norethisterone acetate on days 13-22, and 1 mg of estradiol on days 23-28; n = 21) or transdermal HRT (50 microg/d of estradiol on days 1-28 followed by 250 microg/d of norethisterone acetate on days 14-28; n = 21) for 1 year. Ten female smokers received transdermal HRT for 1 year. MAIN OUTCOME MEASURE(S): Plasma levels of nitrate as an index of nitric oxide production, endothelin-1, and urinary output of the prostacyclin metabolite (2,3-dinor-6-keto-PGF1alpha) and that of the thromboxane A2 metabolite (2,3-dinorthromboxane B2) were measured before and during the combined phases of the 2nd, 6th, and 12th treatment months. RESULT(S): Both regimens increased plasma estradiol levels and alleviated vasomotor symptoms. Neither regimen caused significant changes in nitrate, endothelin-1, prostacyclin, or thromboxane A2 in nonsmoking women. Female smokers had significantly higher levels of endothelin-1, which were significantly reduced by transdermal HRT at 6 months of treatment. CONCLUSION(S): Nitric oxide, endothelin-1, prostacyclin, and thromboxane A2 are not of primary importance in the protective effect of sequential oral HRT against cardiovascular disorders in otherwise healthy nonsmoking postmenopausal women. In this regard, transdermal HRT appears comparable to oral HRT. Postmenopausal female smokers have high levels of endothelin-1 that are reduced by transdermal HRT.

Clinical performance and endocrine profiles of contraceptive vaginal rings releasing 3-keto-desogestrel and ethinylestradiol.

The clinical performance and endocrine profiles of contraceptive vaginal rings (CVR) with an in vitro daily release rate of 15 micrograms of ethinylestradiol combined with 75, 100 or 150 micrograms 3-keto-desogestrel were evaluated. Two studies were performed; one with 11 volunteers, consisting of a control cycle, a cycle with an oral preparation (Marvelon), followed by two CVR treatment cycles, and a second study with 12 volunteers, having the same design but one CVR treatment cycle. A dose-response relationship was seen in the endocrine and clinical performance of the CVR. With CVR 75/15, ovulation occurred in two subjects, and increases in serum estradiol concentrations were seen in two additional subjects. With CVR 100/15, slight estradiol increases were seen in four subjects, but progesterone remained low. With CVR 150/15, both estradiol and progesterone serum concentrations remained low. With CVR 75/15 extra bleeding was common, but with CVR 150/15 this did not occur. No major side effects occurred, and no abnormal Papanicolaou smears or histological findings of the endometrium were found. All volunteers completed all cycles, and the three-week CVR use was generally well accepted. In conclusion, the release rate of CVR 75/15 was insufficient. A vaginal ring with a daily release rate between 100 and 150 micrograms of 3-keto-desogestrel in combination with 15 micrograms of ethinylestradiol seems suitable for contraceptive purposes, and will be further tested in larger clinical studies.

Paraquat embryotoxicity in the Xenopus laevis cleavage phase.

The high Paraquat (PQ, 1-1'-dimethyl-4,4'bipyridylium dichloride) embryotoxicity in Xenopus laevis has been shown to be due to its rapid reduction and instantaneous re-oxidation which produces a reactive oxygen species, ROS. Nevertheless, PQ did not show any effects before hatching, stage 32, which showed a resistance, in early X. laevis development, to oxidative damage. Moreover, in view of its genotoxic properties in several experimental models, we studied PQ in the X. laevis cleavage phase that, characterized by a series of rapid mitotic divisions, might be damaged by genotoxic compounds. Embryos were exposed to 20, 40, 60, and 80 mg/l PQ concentrations from stage 2 to stage 9, and then left to develop in control FETAX solution until stage 47. The 80 mg/l PQ concentration gave 19% embryo mortality at the end of the exposure time, and 16.7% larvae mortality at the end of the test; both values were statistically different from the control, 5 and 6.8% respectively. These results confirmed the high resistance in early X. laevis development to PQ oxidative damage. The malformed larva percentages in the PQ exposed groups were higher as regards the control value but did not show any concentration-response; the most frequent malformed larvae found were affected by abnormal tail flexure coupled with abnormal gut coiling. A further experiment was carried out using the same methodology, but exposing embryos only to the 80 mg/l PQ concentration. The surviving blastulae were embedded in Paraplast, then the slides were stained with 4',6-diamidino-2-phenylindole (DAPI) and the nuclei were examined with a confocal microscope. This new preliminary procedure did not reveal any significant presence of micronucleated micromeres in PQ exposed blastulae with respect to the control. Nevertheless, the mechanism by which PQ induced abnormal tail flexure after cleavage exposure remained unknown. PQ seemed to pass through the jelly coats and vitelline membrane, but it expressed teratogenicity between the 2nd and 3rd day. PQ might be accumulated in the embryos during the exposure, and might express teratogenicity later, but it did not seem to induce genotoxicity during the cleavage phase of X. laevis even at very high concentrations.

Paraovarian/paratubal cysts: comparison of transvaginal sonographic and pathological findings to establish diagnostic criteria.

OBJECTIVES: To describe the sonographic features of paraovarian cysts and to compare these features with pathological findings in order to define the best treatment options (surgical vs. conservative). METHODS: Fifty patients (mean age 48 (range, 14-68) years), each with a surgically proven paraovarian cyst, were retrospectively recruited. Preoperative transvaginal ultrasonographic B-mode and power Doppler observations were re-evaluated and histological reports were analyzed. RESULTS: All cysts were correctly diagnosed as paraovarian at preoperative transvaginal sonography (TVS). Paraovarian cysts appeared as unilocular ('simple') cysts in 33 (66%) cases and multilocular in two (4%). In 15 patients (30%) the cyst showed a variable number of papillary projections growing from the cyst wall (unilocular-solid cysts). Power Doppler examination of the papillae showed the presence of blood vessels in four of these patients (27%). Histological analysis of the masses containing papillary projections diagnosed eight cystadenofibromas, five cystadenomas and two serous papillary borderline tumors, while analysis of paraovarian cysts without papillations revealed benign, serous cysts of paramesonephric or mesothelial origin. CONCLUSIONS: Paraovarian cysts can show a wide range of sonographic features. Their risk of malignancy is low if no papillary projections are detected at transvaginal sonography, but when mural proliferations are present a borderline tumor can be found at pathological examination.

Transvaginal sonographic features of peritoneal carcinomatosis.

OBJECTIVES: Peritoneal carcinomatosis involves the dissemination of intra-abdominal tumor tissue often associated with gynecological malignancies. The objective of this study was to describe the transvaginal sonographic appearance of this condition. METHODS: The data of 60 patients with surgically and histologically proven peritoneal carcinomatosis were analyzed. Transvaginal sonograms performed within 7 days of admission to the operating theater were re-evaluated in order to identify the sonographic features associated with peritoneal carcinomatosis. RESULTS: Carcinomatosis was revealed in 53/60 cases (88%) by the presence of hypoechoic nodules attached to the peritoneum and visible on transvaginal sonography (TVS). The pouch of Douglas was the site most frequently involved. Power Doppler sonography showed the presence of blood vessels in 48 (91%) of these metastases. Ascites was found in 50 (83%) women. An adnexal mass suggestive of being the primary tumor was present in only 41 women (68%). CONCLUSIONS: Peritoneal carcinomatosis has typical features on TVS and, in the vast majority of cases, its genital origin can be correctly hypothesized. Power Doppler sonography strengthens the diagnosis by showing vascularity of the peritoneal implants. In a patient with a known pelvic malignancy or whenever peritoneal carcinomatosis is suspected, TVS can give useful information in order to better assess the presence and extension of metastatic nodules within the abdominal cavity.

Can the status of tubal pregnancy be predicted with transvaginal sonography? A prospective comparison of sonographic, surgical, and serum hCG findings.

Results of transvaginal sonography were compared prospectively with surgical findings and levels of serum human chorionic gonadotropin in 120 women with a proved tubal pregnancy. The most common sonographic finding was a saclike adnexal ring, which was seen in 74 of the women (61.7%). This finding was strongly associated with functioning trophoblasts and with an intact fallopian tube. In 39 of the women (32.5%) an adnexal mass with a complex texture was found. Of these 39 women, 20 had a tubal hematoma and six had a ruptured fallopian tube. The size of the tubal mass created by ectopic pregnancy was predicted precisely (r = .91, P less than .001), and transvaginal sonography enabled detection of hemoperitoneum with a sensitivity of 91% (68 of 75 women). This study suggests that the status of a tubal pregnancy can be predicted reliably on the basis of transvaginal sonographic findings.