INTERCEED(TC7) (Johnson & Johnson Patient Care Inc., New Brunswick, NJ) is an absorbable fabric specially designed to reduce postsurgical adhesions. The authors report on a prospective, randomized, multicenter, clinical trial that evaluated the efficacy of Interceed in reducing adhesions in humans. Infertility patients (n = 74) with bilateral pelvic sidewall adhesions were studied at treatment laparotomy and "second-look" laparoscopy to determine Interceed's effectiveness. After removal of adhesions at laparotomy, the deperitonealized area of one pelvic sidewall was covered with Interceed. The contralateral untreated sidewall served as the control. Pelvic sidewalls covered with Interceed had a 90% improvement over control sidewalls in preventing adhesion formation. Additionally, Interceed treatment was associated with a 57% reduction of the extent of adhesion formation over that obtained by microsurgical techniques alone. Interceed also provided a significant benefit in reducing the severity of those adhesions that did form, and significantly reduced the number of adhesions between the ovary and pelvic sidewall. In conclusion, Interceed significantly reduced the incidence, extent, and severity of postsurgical pelvic adhesions.
InfertilityClomiphene CitrateLuteal Phase AssessmentDiagnosis and Treatment
Eighty-seven patients who underwent a late secretory phase endometrial biopsy while taking clomiphene citrate (CC) for ovulation induction were studied. Of the endometrial biopsies, 21 (24%) showed an endometrium greater than 2 days out of phase (OOP) with respect to the subsequent menstrual cycle. All 87 patients were categorized by age, weight, CC dosage, and underlying disease entity. The patients then were evaluated by these categories in relation to the incidence of an OOP biopsy while taking CC. Patients with a diagnosis of hypothalamic amenorrhea were statistically more likely to have an OOP endometrium. No other subgroup showed an increased or decreased incidence of OOP biopsies. Conception and spontaneous abortion rates were similar among patients with in-phase biopsies and those with out-of-phase biopsies, which subsequently were corrected with further medical therapy. An aggressive approach to the diagnosis and treatment of luteal phase insufficiency in patients who receive CC for ovulation induction is recommended.
Mammalian spermatozoa must undergo many changes to be able to fertilize the oocyte. One of these changes, the acrosome reaction, has been established as a requisite for gamete membrane fusion to occur; it consists of the fusion and vesiculation of the sperm plasma membrane with the outer acrosomal membrane of the principal segment of the acrosome. Reaction of the equatorial segment has occasionally been observed. The objective of the present work was to determine whether the presence of the sperm plasma membrane over the equatorial segment is necessary for gamete membrane fusion to occur. Golden hamster spermatozoa were capacitated in vitro in TAPL 10K, and the maximum possible percentage of acrosome reaction was determined at 82.79% + 1.69% SD (P = 0.27; r = 0.21). Ultrastructural studies showed that 93.6% of the reacted spermatozoa in this population had their principal and equatorial segments reacted. The fertilizing ability of these spermatozoa was assayed using zona-free hamster oocytes. The percentage of fertilized ova obtained was 98.8% (308/312). Ultrastructural studies showed the presence of spermatozoa with reacted equatorial segment inside the cytoplasm of immature oocytes. The evidence presented in this work demonstrates that the plasma membrane of spermatozoa with reacted equatorial segment retains its ability to fuse with the oocyte.
C-reactive protein (CRP) is an acute-phase protein synthesized by the liver during the course of a large number of diseases. During gestation and parturition, progressively increasing numbers of gravida develop elevated levels up to 32, 48 to 80 per cent, respectively). These elevations in pregnancy, the nonspecificity of the test, and the inability to function as a reliable marker of fetal and/or maternal infectious morbidity have obscured the pragmatic utility of CRP determinations in both obstetrics and gynecology. Because of its biophysical kinetics, C-reactive protein determinations are best used as a monitoring parameter after the documentation of infection rather than as a diagnostic indicator of infection. They can provide valuable end titration points for termination of parenteral antibiotic therapy.
Borenstein R et al., 1989·Aust N Z J Obstet Gynaecol
Fourteen pregnancies were achieved with tamoxifen therapy in 12 women who failed to conceive with clomiphene citrate. There were no side-effects and fewer treatment cycles were required than with clomiphene citrate treatment. Ovulation and cervical score with tamoxifen therapy were significantly higher (p less than 0.005).
Sixty-three endometrial biopsies were dated histologically by using the standard criteria on two separate occasions by the same observer. Overall, it was found that exact agreement occurred in 15 (24%), but disagreement of more than 2 days occurred in 6 (10%). The proportion of exact agreement in the first half of the luteal phase (32%) was found to be significantly higher (P less than 0.05) than that in the second half of the luteal phase (9%). In a separate part of the study, 27 women had two endometrial biopsies, each performed in a separate cycle. The within-subject between-cycle variation of the results of endometrial dating (exact 4%, disagreement of more than 2 41%) was found to be significantly different from intraobserver variation (P less than 0.01 for both). The amount of intraobserver variation suggests that the traditional dating criteria are not precise enough to quantify corpus luteum function in the second half of the luteal phase, whereas the amount of within-subject between-cycle variation implies that the result of endometrial dating in one cycle cannot be used reliably to predict that of another cycle.
General OB/GYNInflammatory MarkersC-Reactive ProteinInfectious Morbidity
We tested the hypothesis that disturbed follicular development and disturbed luteal progesterone (P4) secretion are associated with reduced gonadotropin secretion in the early follicular phase by measuring pulsatile LH and FSH secretion at that time in 53 normally menstruating women. Three groups of women were identified on the basis of serum sex steroid concentrations (measured daily throughout the cycle) and luteal phase length. Group A (n = 27) had normal ovarian hormone secretion with peak serum estradiol (E2) concentrations of 440 pmol/L or more, peak serum P4 concentrations of 19 nmol/L or more, and luteal phase length of 9 days or more. Group B (n = 16) had normal peak serum E2 values, but peak serum P4 values less than 19 nmol/L and/or luteal phase length less than 9 days. Group C (n = 10) had peak serum E2 values below 440 pmol/L. Risk factors for the disturbances found in groups B and C were exercise and/or intermittent dieting. Compared to group A, both groups B and C had reduced mean serum LH concentrations (3.1 +/- 1.5 vs. 2.3 +/- 1.4 and 2.0 +/- 1.0 IU/L; P less than 0.05) and reduced LH pulse frequencies (5.2 +/- 2.1 vs. 3.5 +/- 1.8 and 3.3 +/- 2.3 pulses/12 h; P less than 0.02). LH amplitude was similar in all 3 groups. Mean serum FSH concentrations were slightly but not significantly lower in group C. We conclude that reduced gonadotropin secretion during the follicular phase may indeed affect E2 and P4 secretion at later stages of the menstrual cycle. The patterns of alteration associated with disturbed E2 and P4 secretion in normally menstruating women are similar to those that occur in women with hypothalamic amenorrhea.
Reproductive EndocrinologyOvarian-Pituitary AxisGonadotropin RegulationMaturation and Shedding
The relationship between asymptomatic bacteriuria and prematurity/low birth weight (LBW) is still a controversial issue, despite many studies. Meta-analysis, a research tool designed to analyze and combine the results of previous studies, may resolve this discrepancy among contradictory results of clinical trials. The purpose of this study was to examine the relationship between asymptomatic bacteriuria and preterm delivery/LBW using meta-analysis. Reports from the literature were classified according to study design into cohort or randomized-treatment control trials. Meta-analysis of cohort studies showed that untreated asymptomatic bacteriuria during pregnancy significantly increased rates of LBW and preterm delivery. Nonbacteriuric patients had only about two-thirds the risk (typical relative risk = 0.65; 95% confidence interval 0.57, 0.74) of LBW and half the risk (typical relative risk = 0.50; 95% confidence interval 0.36, 0.70) of preterm delivery of those with untreated asymptomatic bacteriuria. These reduced risks correspond to a 3.4 (confidence interval 1.8, 5.0) percentage-point difference in LBW and a 3.8 (1.1, 6.4) percentage-point difference in preterm delivery. The analysis of randomized clinical trials showed that antibiotic treatment significantly reduced the risk of LBW (typical relative risk = 0.56; 95% confidence interval 0.43, 0.73), with a substantial reduction of 6.4 (confidence interval 3.3, 9.5) percentage points in the rate of LBW. We conclude that clinical and epidemiologic evidence indicates a strong association between untreated asymptomatic bacteriuria and LBW/preterm delivery and that antibiotic treatment is effective in reducing the occurrence of LBW.
Ultrasound (US) has been demonstrated to be the method of choice for diagnosing luteinized unruptured follicle syndrome and to be a valuable adjuvant in the assessment of luteal phase defect. In this prospective study, the use of US with postcoital testing (PCT) is evaluated. Fifty control infertility patients were examined with serial US for follicle dynamics in conjunction with PCT. Standard curves for follicle dynamics versus cervical mucus quality (Insler score) were calculated. Eighteen patients referred for abnormal mucus underwent similar evaluation. Their follicle dynamics versus mucus quality were compared with those of the controls. (1) there is a predictable relationship between follicle size and mucus quality, (2) the majority of patients with abnormal mucus have normal follicular dynamics, and (3) a minority of patients with abnormal mucus have either a narrow mucus window or abnormal follicular dynamics. In addition, US was found to be cost-effective in the overall fertility evaluation.
InfertilityDiagnostic EvaluationLuteal Phase ProfilesLuteal Phase Dating
The authors have further analyzed women diagnosed as having luteal phase insufficiency in hope of determining the value of specific screening tests as well as determining the degree of heterogeneity of pathophysiologic mechanisms involved in the disorder. Twelve women with the disorder were identified, 6 with two consecutive midluteal serum progesterone (P) levels less than 10 ng/ml (group 1) and 6 with two consecutive late luteal phase endometrial biopsies out of phase (group 2); 4 infertile women with normal serum P and late luteal biopsies also were studied (group 3). All underwent serum sampling for P and luteinizing hormone (LH) at 20-minute intervals for 24 hours, beginning at 9:00 A.M. of day 7 post-LH surge. No significant differences were noted among the three groups for LH area under the curve, pulse frequency, or pulse amplitude. Furthermore, no differences were ascertained for P area under the curve. However, individuals were identified who had one or more hormonal abnormalities but no abnormal biopsy, as well as patients with normal hormonal profiles but having abnormal endometrial development. Receiver Operating Characteristic curves demonstrated that pooled morning serum P levels provided optimal predictive ability of biopsy results. The authors conclude that luteal phase insufficiency is a heterogeneous disorder, and that neither endometrial biopsy nor serum hormonal analysis obviates the need for the other.
InfertilityDiagnostic CriteriaAccuracy and ReproducibilityReference Standards
Five regularly menstruating women of proven fertility, with normal prolactin and thyroid function studies, underwent a total of 39 endometrial biopsies (EMBs). The slides were dated in blinded fashion, and the cycle date determined by considering the date of the next menstrual period as day 28 and counting backward. Using a 2-day or greater lag in endometrial maturity to define a luteal phase defect (LPD), the incidence of single and sequential out-of-phase EMBs was 51.4% and 26.7%, respectively. Using a 3-day or greater lag to define a LPD, the incidence of single and sequential out-of-phase EMBs was 31.4% and 6.6%, respectively. These incidences in normal, fertile women are as high as the rates quoted for infertile populations, and call into question the standard criteria for defining this condition and evaluating therapies to correct it.
Reproductive EndocrinologyNeuron Development and MigrationEmbryologyKallmann Syndrome
Neurons expressing luteinizing hormone-releasing hormone (LHRH), found in the septal-preoptic nuclei and hypothalamus, control the release of gonadotropic hormones from the anterior pituitary gland and facilitate reproductive behaviour. LHRH-expressing neurons are also found in the nervus terminalis, a cranial nerve that is a part of the accessory olfactory system and which projects directly from the nose to the septal-preoptic nuclei in the brain. During development, LHRH-immunoreactivity is detected in the peripheral parts of the nervus terminalis before it is found in the brain. Using a combination of LHRH immunocytochemistry and tritiated thymidine autoradiography in fetal mice, we show that LHRH neurons originate in the medial olfactory placode of the developing nose, migrate across the nasal septum and enter the forebrain with the nervus terminalis, arching into the septal-preoptic area and hypothalamus. Clinically, this migratory route for LHRH-expressing neurons could explain the deficiency of gonadotropins seen in 'Kallmann's syndrome' (hypogonadotropic hypogonadism with anosmia).
PregnancyInfection BiomarkersTocolysis OutcomesC-Reactive Protein in Pregnancy
Tocolytics were administered in 66 consecutive women in uncomplicated preterm labour with intact fetal membranes (53 singleton and 13 twin pregnancies). C-reactive protein (CRP), a marker of infection, was determined daily and used retrospectively to investigate the role of subclinical infection in preterm labour and to predict the efficacy of tocolysis and the development of a clinical perinatal infection. CRP was also determined in 66 women in uncomplicated labour at term (53 singleton and 13 twin pregnancies). The placenta was examined for histological evidence of infection in all patients who were delivered before 36 weeks (n = 21) and in all women in the control group (n = 66). Elevated CRP levels were more often found in patients who were refractory to tocolysis, suggesting an underlying infectious morbidity. Placental infection was found in 62% of the preterm delivery group and in 12% of the control group. There was an association between elevated CRP levels and histological evidence of placental infection. However, confounding factors such as urinary tract infections limit the usefulness of the CRP test. Because CRP cannot predict clinical perinatal infection accurately, its clinical relevance is very limited.
Contraception/ComparisonGastrointestinal Side EffectsInflammatory Bowel Disease RiskProspective Cohort
Data from the Royal College of General Practitioners Oral Contraception Study have been examined to determine whether oral contraceptive use was associated with the development of Crohn's disease or ulcerative colitis. Over a 17 year period Crohn's disease developed in 42 women and ulcerative colitis in 78. The incidence of both diseases was greater in oral contraceptive users compared to non-users with the rate ratio for Crohn's disease being 1.7 (95% confidence limits, 0.88, 3.2) and for ulcerative colitis being 1.3 (95% confidence limits 0.82, 2.0). For both diseases incidence was unrelated to parity or social class, but women smoking at recruitment had a greater incidence of Crohn's disease (rate ratio 1.8, 95% confidence limits 0.93, 3.3) and a reduced incidence of ulcerative colitis (rate ratio 0.68, 95% confidence limits 0.41, 1.1). Although these results are based on small numbers and could be chance findings, they are consistent with other studies showing associations between oral contraceptive use, smoking and the development of Crohn's disease and ulcerative colitis.
InfertilityClomiphene Citrate Side EffectsAnti-Estrogen EffectsEndometrial Thickness Monitoring
Fifteen ovulating women had serial ultrasound scans to measure follicular, endometrial, and uterine growth, as well as biochemical indices including estradiol (E2) and the free androgen index, throughout a natural and a clomiphene-citrate-induced cycle. Despite higher E2 levels in the 5 days preceding ovulation, the clomiphene cycles were characterized by absence of the normal increase in uterine volume and an inhibition of endometrial thickening. It is proposed that the anti-estrogen effect of clomiphene inhibits the normal cyclical growth of the uterus and endometrium.
The clinical and hormonal response to 12-month therapy with the antiandrogen, spironolactone, in conjunction with near-physiologic doses of female gonadal steroids in 50 transsexual males, is presented. An unselected referred series of 61 men with the psychiatric diagnosis of transsexualism was treated; 10 subjects who had received previous gonadal surgery and 1 man with Klinefelter's syndrome were excluded. Twenty-seven conventionally treated (CT; high-dose estrogen), age 34.4 +/- 10.5 years, mean +/- SD, and 23 untreated patients (SPS), age 30.7 +/- 6.2 years, were studied. Following the initial visit, all 50 were begun on spironolactone and low-dose female hormone therapy. Despite high-dose estrogen treatment for more than 2 years, the mean testosterone (T) level for the CT group was not in the female range (169 +/- 193 ng/dl; normal 20-80). Spironolactone, in doses of 200-600 mg/day, lowered T to the female range in both groups after 12 months (CT 87 +/- 111 and SPS 49 +/- 41 ng/dl). This was achieved in the CT group despite decreases in estrogen dose and discontinuation of parenteral therapy. SPS subjects experienced significant decreases in plasma T (642 +/- 236 to 49 +/- 41 ng/dl, p less than 0.001). Systolic blood pressure dropped (128 +/- 14 to 121 +/- 14 mm Hg, p less than 0.05). The clinical response, including decreased male pattern hair, breast development, feminization, and lack of erections was excellent in most subjects.
Menstrual CycleExercise-Associated AmenorrheaLH PulsatilityCortisol and Reproductive Function
The functional integrity of the hypothalamic-pituitary-ovarian and hypothalamic-pituitary-adrenal axes was assessed by determining pulsatile LH, ACTH, and cortisol secretion during the early follicular phase in athletic women with regular menstrual cycles (CA; n = 9), athletic women with amenorrhea (AA; n = 9), and regularly cyclic sedentary women (CS; n = 8). The CA and AA women were not significantly different in body composition, exercise training, psychometric tests, or dietary consumption. The CA women had shorter luteal phases (P less than 0.05) and lower urinary excretion of pregnanediol glucuronide than the CS women. In the AA women, urinary estrone glucuronide, pregnanediol glucuronide, and LH excretion were low throughout a 30-day period. The CA women had a 24-h pattern of pulsatile LH secretion characterized by reduced frequency (P less than 0.05) and increased amplitude (P less than 0.05), yielding an overall increased 24-h mean level (P less than 0.05), but interpulse intervals similar to those in the CS women. During sleep, LH pulse frequency slowed in the CS and CA women, while pulse amplitude increased and the mean serum LH level decreased in both groups. The AA women had even fewer pulses (P less than 0.05) of normal amplitude occurring at much more variable (P less than 0.01) interpulse intervals. Sleep-associated changes in LH pulsatility were absent. Responses to a 10-microgram bolus GnRH dose revealed blunted (P less than 0.05) FSH release in CA and augmented (P less than 0.05) LH release in AA women. The groups did not differ in any 24-h ACTH pulse pattern parameter or in cortisol pulse frequencies. Yet, early morning (0200-0800 h) serum cortisol levels were higher (P less than 0.05) in both groups of athletes, and this elevation was extended through the day (0800-2000 h; P less than 0.001) and evening (2000-0200 h; P less than 0.05) in the AA women. The plasma ACTH and serum cortisol responses to bolus human CRH administration were blunted in the CA and AA women [change from baseline (delta) in ACTH, P less than 0.05 and P less than 0.01; delta cortisol, P less than 0.01 and P less than 0.01, respectively], but adrenal sensitivity (delta cortisol/delta ACTH ratio) was increased (P less than 0.05). The plasma ACTH and serum cortisol responses to meals also were blunted in the athletic groups (P less than 0.05).(ABSTRACT TRUNCATED AT 400 WORDS)
Oral clomiphene citrate (CC) and vaginal progesterone suppositories (PS) are common treatment modalities in luteal phase dysfunction (LPD). Little is known regarding the relative efficacy of these agents. To study the use of CC and PS in the management of LPD, a retrospective cohort study of patients presenting with infertility was undertaken. Sixty-five patients in whom LPD was diagnosed and corrected, as judged by endometrial biopsies, were studied; 35 were treated with PS and 30 with CC. Using Student's t-tests and chi-square analyses, the two treatment groups were demographically comparable. Using life-table analysis, no one therapeutic approach proved superior. Clomiphene citrate and PS are comparable treatment modalities in the setting of LPD given correction of endometrial lag.
Menstrual CycleEndometrial DatingUltrasound vs Hormonal MethodsProgesterone and Estradiol Secretion
Dating of maturity of the endometrium by histologic examination was correlated with four methods of ovulation detection in 13 cycling parous women. Histologic dating was assessed independently by two pathologists and correlated with the postovulatory duration as determined by daily transvaginal ultrasound scanning, serum LH measurements, basal body temperature (BBT), and subtraction of 14 days from the onset of menses. In addition, progesterone and estradiol (E2) were measured in daily serum samples. Dating of the endometrial biopsy was highly correlated (P less than .002) with the day of ovulation as determined by ultrasound, and was found to be within 2 days of the correct postovulatory day on evaluation of 25 of 26 (96.1%) of the interpretations. The accuracy of dating using the LH surge was 84.6% (22 of 26 interpretations), and with the BBT thermogenic shift was 76.9% (20 of 26 interpretations). However, dating of the endometrium was within 2 days of the correct day in only 17 of the 26 interpretations as determined by subtracting 14 days from the onset of the subsequent menses. The accuracy of dating was significantly better correlated (P less than .025) with days from ovulation as determined by ultrasound than as calculated from the onset of menses. There was a significant correlation between endometrial dating and the amount of progesterone (P less than .01) and E2 (P less than .01) secreted from the day of ovulation, as determined by transvaginal ultrasound, to the day of biopsy. These data confirm a strong correlation between endometrial dating and ovarian hormone secretion during the postovulatory phase.(ABSTRACT TRUNCATED AT 250 WORDS)
EndometriosisGnRH Agonist TherapyOvarian Suppression and Bone DensityDanazol
Lumbar bone mineral density (BMD) was evaluated by dual photon absorptiometry (DPA) in 38 women with laparoscopically diagnosed and staged endometriosis. DPA was performed before and at the completion of 26 weeks of treatment with either gonadotropin releasing hormone agonist (GnRHa) or danazol. Twenty-five women received GnRHa either nasally or subcutaneously and 13 women received danazol 200 mg four times daily by mouth. During treatment amenorrhea and suppressed estradiol levels were observed in all patients. Each patient took a supplement of oral calcium 1 gm daily. DPA (reproducibility +/- 1.5%) was read by a single observer unaware of the treatment assignment of the patient. The mean (+/- standard error) of the entire group prior to treatment was 98.8% +/- 0.03% of a control population of women from the same geographic area matched for race, age, and weight. At the completion of treatment, BMD was slightly decreased in the GnRHa group and marginally increased in the danazol group but neither change was significant. Women with endometriosis have lumbar BMD in the normal range and ovarian suppression with either GnRHa or danazol produces no significant change in BMD.
Sonographic visualization of the cumulus oophorus or of morphologic alterations in the wall of the dominant follicle have been reported to be reliable signs of imminent ovulation when conventional transabdominal sonography is used. To determine if transvaginal sonography could allow a more frequent and confident prediction of imminent ovulation, we prospectively monitored 22 ovulatory menstrual cycles in four women undergoing artificial insemination and in 13 normally menstruating volunteers. Scanning was done on alternate days in the periovulatory period; a 7.5-MHz transvaginal transducer was used. Despite the improved resolution obtained with transvaginal sonography, confident identification of the cumulus oophorus or of mural changes in the follicle was not possible in any of the cycles followed. No other consistent follicular characteristic predicted imminent ovulation. We conclude that confident prediction of imminent ovulation is not possible with sonographic analysis.
PregnancyExercise During PregnancyExercise-Associated AmenorrheaPhysical Activity and Reproduction
Two runners who were not aware they had conceived continued their intense running regimens during the first and second trimesters of pregnancy. Both women assumed that their amenorrhea was due to endurance training. When their pregnancies were diagnosed, both women markedly reduced their training mileage during the third trimester because they feared that intense exercise might harm the fetus. Retrospective data were collected on their antenatal and intrapartum courses. Both women delivered healthy infants of normal weight. Although these two cases suggest that strenuous anaerobic exercise during pregnancy is not harmful, more studies are needed to determine if these cases are isolated.
Domingo JL, 1989·Reviews of Environmental Contamination and Toxicology
Cobalt is an essential trace element which is widely distributed in nature. Most of cobalt consumed is used in the manufacture of alloys, and although not released extensively in the environment, it may represent a hazard to human health. In addition, excess dietary cobalt produces toxic effects in animals. Polycythemia and hyperglycemia with transitory damage to pancreatic alpha-cells have been widely reported after cobalt administration. Cobalt salts induce respiratory deficiency in yeast. CoCl2 increased sister chromatid exchange (SCE) in P388D1 cells and in lymphocytes from two donors. So far it has not been possible to induce cancer in experimental animals using cobalt by any other route than by injection. Ingestion of cobalt may lead to reproductive changes in the male rat such as loss of testicular volume and darkening of testicle color. On the other hand, oral administration of cobalt did not produce teratogenicity or significant fetotoxicity in the rat at daily doses as high as 100 mg CoCl2/kg. However, cobalt affected the period of late gestation as well as the postnatal development of the pups. Occupational toxicology of cobalt, hygienic and epidemiologic aspects, and treatment of cobalt poisoning are also topics of special interest. Cobalt is a metal with marked allergenic potential. Asthma, interstitial lung disease and combined asthma and alveolitis have been described as occupational health hazards. EDTA, DTPA, and N-acetyl-L-cysteine have been suggested as possible antidotes in cobalt intoxication.
Traditional therapies for abnormal cervical mucus, other than timed intrauterine insemination, are noteworthy for being ineffectual. Patients (n = 27) with documented abnormal Insler scores in repetitive cycles and failure to conceive with traditional treatments were screened with conjugated equine estrogens (CEE) for estrogen responsiveness of the cervix. Only 5 patients were found unresponsive. Seventeen patients with CEE-responsive cervices then were treated with human gonadotropins (hMG), initially 1 ampule days 5 to 11. If the mucus failed to improve, the hMG was increased to standard doses. Eight patients responded to 1 ampule hMG with improved mucus and conception. The remainder required 2 ampules hMG. In patient cycles with corrected cervical mucus, the viable fecundibility (fv) was 0.35. This is significantly higher than predicted for this population (fv = 0.09; P less than 0.01). In all, 14 of 17 patients conceived viable pregnancies during hMG treatment. It is concluded that graduated hMG is efficacious in treating patients with abnormal cervical mucus responsive to CEE. It is preferable to either in vitro fertilization or gamete intrafallopian transfer, based on both cost and efficacy for most patients.
PregnancyMenstrual Dating AccuracyUltrasound vs Menstrual DatingPostterm Pregnancy Diagnosis
Despite recognition that estimation of gestational age (GA) based on maternal recollection of the last normal menstrual period (LNMP) is fraught with error, it is not generally appreciated that the magnitude and direction of this error vary as a function of the LNMP estimate. Early second-trimester (16 to 18 weeks) ultrasound determinations of the fetal biparietal diameter were used as the "gold standard" to test the validity of LNMP-based GA estimates in 11,045 women. The large majority of deliveries occurring at or near term showed LNMP estimates that were valid within plus or minus seven days of the ultrasound estimate. As the LNMP GA deviated progressively toward earlier or later GAs, however, the discrepancies became quite marked, especially for postterm dates. The positive predictive values of the LNMP GA estimates decreased dramatically from term (.949) to preterm (.775) to postterm (.119) deliveries. These systematic errors in menstrual GA estimates have profound implications for unnecessary induction, dysfunctional labor and cesarean section, and resultant neonatal and maternal morbidity.
Endometrial biopsy specimens (n = 62) were evaluated by five pathologists to assess the effect of interobserver variation on histologic dating of the endometrium. The potential effect of this variation on the diagnosis of luteal phase defects (LPDs) and resulting clinical management was also determined. Mean (+/- standard error) interobserver variation was 0.96 +/- 0.08 days, comparable to results reported by other investigators. The magnitude of the variation was not affected by whether the biopsy specimen was obtained in the mid or late luteal phase, the degree of lag between the dating and subsequent menses, or the presence of an LPD. Redating of a specimen by another pathologist would have resulted in a change in the determination of "in" or "out" of phase in 22% of cases. The subsequent probability of changing patient management altered ranged from 22% to 39% depending on the clinical setting.
Reproductive EndocrinologyLuteinized Unruptured FollicleAnovulation MechanismsFollicle Rupture and Luteinization
DlJ. ring the last stage of puberty, the hypothalamic-pituitary-ovarian axis acquires the ability to respond to high levels of estradiol; this results in a sharp increase in the pituitary output of luteinizing hormone (LH). It is believed that within a mature follicle, the LH surge triggers a complex set of events that results in two apparently ovulation and luteinization. The term ovulation will imply rupture of the follicular wall and release of an oocyte, whereas luteinization will imply the morphologic and biochemical shift in the …
Pregnancy outcomes were evaluated retrospectively in 350 women to investigate the relationship between endometriosis and spontaneous abortions. The frequency of spontaneous abortions in women with endometriosis was significantly higher than in both a fertile nonendometriosis group and an infertile group with tubal disease. There was no correlation between the severity of the endometriosis and the frequency of spontaneous abortions. After treatment, the frequency of spontaneous abortions was significantly decreased in both the endometriosis and the tubal disease group, but these values were not significantly different from each other. We conclude that high spontaneous abortion rates are a characteristic of other subgroups of women with secondary infertility and not just in women with endometriosis, and that the majority of spontaneous abortions associated with endometriosis are not caused by the condition.
Nine patients in preterm labor requiring long-term tocolysis were managed with subcutaneous terbutaline administered via a portable infusion pump. All had failed oral tocolytic therapy and were therefore faced with prolonged hospitalization. In this feasibility study, the patients were treated at home and monitored with portable tocodynamometers and home nursing visits. Uterine activity data were transmitted via telephone to the study center and terbutaline pump infusion rates were adjusted accordingly. Terbutaline pump therapy consisted of a combination of low-dose continuous basal infusion supplemented with intermittent high-dose boluses. Total daily drug dosage remained exceptionally low (less than 3 mg/24 hours). The mean gestational age at initiation of therapy was 29.6 +/- 3.7 weeks, and pregnancy was prolonged an average of 9.2 +/- 4.3 weeks. The minimum gestational age at delivery was 37.3 weeks. Patient tolerance was excellent and, in a total 394 patient-days of therapy, there were no significant complications. We conclude that the portable subcutaneous terbutaline pump may be a promising new method for long-term outpatient tocolysis in patients who cannot be maintained on oral therapy.
Reproductive EndocrinologyOral Administration PharmacologyMetabolites and Side EffectsProgesterone Effects
Progesterone and its metabolites were measured in serum extracts by radioimmunoassay and gas chromatography-mass spectrometry, respectively, after ingestion of micronized progesterone by eight postmenopausal women. One subject received 400 mg of micronized progesterone orally that induced a hypnotic state that lasted for approximately 2 hours. Blood samples were drawn periodically from all subjects for measurement of progesterone and its metabolites in serum. Levels of serum progesterone and its metabolites increased significantly from baseline values and reached a peak between 2 and 6 hours after oral progesterone administration. Significant quantities of five compounds (progesterone, 5 alpha-pregnan-3 alpha-ol-20-one, 5 beta-pregnan-3 alpha-ol-20-one, 5 beta-pregnan-3 alpha,20 beta-diol, and 5 beta-pregnan-3 alpha-ol-11,20-dione) that have been reported to possess anesthetic qualities were identified. The sedative and hypnotic effects of oral administration of progesterone may be mediated through those compounds.
Women can accurately predict the day of ovulation by examining vaginal mucus using the Billings Ovulation Method (BOM). they then can choose to either have sexual intercourse if they wish to conceive or to refrain if they do not want to become pregnant by being able to identify the peak day of fertility and the 3 following days of diminishing fertility. A preovulatory phase of the ovulatory cycle follows menstruation which generally includes a sensation of dryness around the genital area but sometimes no dry days occur. At this point progesterone activates the secretion of a thick sticky mucus into the cervical canal which sperms cannot penetrate. This mucus also serves to guard against infection in the reproductive tract and abdominal cavity. When circulating estrogen increases due to follicular development a fluid clear and stringy mucus replaces the thick mucus. this mucus is like a raw egg white. Under the microscope it has a distinctive fern pattern. Sexual intercourse during this time period may result in pregnancy because this mucus sustains sperm cells in cervical crypts for 48-72 hours. Not all women notice the changes in the mucus however but they can sense the vulva as soft swollen and moist. The final day of this sensation identifies the peak day (day 1) in which ovulation customarily occurs. Even though fertility decreases in the next 3 days conception may occur in days 1-3. Infertility sets in on day 4 and last on average 2 weeks. any mucus now seems sticky and opaque. WHO field trials in El Salvador and 4 other countries confirmed that BOM is >99% effective when couples adhere to the guidelines. Research demonstrated that illiterate couples from low socioeconomic status understand it and apply it successfully.
Since 1979, Dr Redwine has performed the near-contact laparoscopy for the removal of endometriosis on nearly 400 women. Data collected from Dr Redwine's follow-up studies indicate that 75% of his patients have experienced complete relief of symptoms, and 20% have experienced an improvement in their symptoms from disabling pain to minimal pain. The individualized perioperative care and the high success rate realized with the near-contact technique has attracted women seeking relief from the painful and sometimes debilitating effects of endometriosis.
Five programs of instruction in the ovulation method (OM) in diverse geographic and cultural settings are described, and characteristics of approximately 200 consecutive OM acceptors in each program are examined. the religious background and family size of acceptors are variable, as is the level of previous contraceptive use. Acceptors are drawn from a wide range of socioeconomic and religious backgrounds; however, family planning intention was similarly distributed in all five countries. In sum, the ovulation method is accepted by persons from a variety of backgrounds within and between cultural setting.
Twenty women with the diagnosis of premenstrual syndrome (PMS) participated in a double-blind, placebo-controlled, crossover study to evaluate the efficacy of naltrexone, an oral opiate antagonist. This study was designed to test the hypothesis that inhibition of opiate withdrawal would aid in the treatment of PMS. The subjects received either placebo or naltrexone from days 9-18 of the cycle for three consecutive cycles. The mean scores of the three day-25 Menstrual Distress Questionnaires of 16 patients on naltrexone were compared with the mean scores of the same patients on placebo. Scores were at least ten points lower on naltrexone in 11 patients and at least ten points higher on naltrexone in two patients. Score changes of less than ten points were noted in the other three patients. The mean scores dropped 28 points on naltrexone (P = .016). The general acceptability of naltrexone was good, with side effects including nausea, decreased appetite, and dizziness. These results suggest that naltrexone alleviates many PMS symptoms and may be an effective treatment for this syndrome.
The low-molecular-mass insulin-like growth factor-binding protein (IGF-BP) and placental protein 12 (PP12) are identical proteins that are present in human serum, amniotic fluid, secretory endometrium and decidua. IGF-BP/PP12 is believed to act as an autocrine or paracrine regulator of cell growth. A cDNA clone encompassing the entire protein coding region of this protein was isolated from a human decidual cDNA library. The authenticity of the cDNA was verified by in vitro transcription/translation experiments and by the identity of the 10 N-terminal amino acids deduced for the mature peptide with those obtained by direct protein sequencing. The amino acid sequence indicates that pre-IGF-BP/PP12 consists of 259 amino acid residues. The putative signal peptide is 25 residues long, and the mature protein thus contains 234 amino acids and has a molecular mass of 25293 Da. The sequence is very cysteine-rich at the N-terminus after which there are regions of clustered Pro, Glu, Ser and Thr residues (so-called PEST regions), which exist in proteins with short half-lives. The amino acid sequence also includes an Arg-Gly-Asp tripeptide that may function as a cell recognition signal. The IGF-BP/PP12 gene encodes a single 1.6 kb mRNA species that is expressed in decidua, secretory endometrium, liver and a human hepatoma cell line (HepG2). Southern blot analysis suggests that there is a single IGF-BP/PP12 gene in the human genome.
Medroxyprogesterone acetate (MPA; Provera) was given orally to 449 women from the 5th to 7th week of pregnancy until at least the 18th week. Data are recorded from two treatment groups (recurrent abortion and threatened abortion) and are compared to a matched series. A total of 1,016 pregnancies are included in the study, and all patients were recruited from a subfertile population conceiving from a range of infertility treatments. Early pregnancy wastage was high throughout the groups and was significantly elevated (43%; P less than .001) in those women who had vaginal bleeding in early pregnancy. The study focuses on the question of potential teratogenicity of progestagens administered in the first trimester. There were 15/366 (4.1%) infants with congenital abnormalities in the MPA-treated group and 15/428 in the untreated group (3.5%). The difference was not significant, and MPA is considered to have no embryopathic risk, nor is it likely to retain an abnormal fetus that might otherwise abort. It appears that MPA is a safe drug to use in pregnancy although the question of efficacy has not been addressed in this report. Considering other recent negative epidemiologic studies with regard to teratogenicity, we add to the conclusion that MPA cannot be demonstrated to have a measurable teratogenic risk and certainly does not present a risk for congenital heart disease and limb reduction defects.
Luteal phase deficiency is an ovulatory dysfunction problem that is subtle but real. It may be the most common ovulatory problem in women. Luteal phase deficiency has been clearly demonstrated in the research setting (1) in spontaneous cycles, (2) when follicular maturation has been impeded, and (3) when luteotrophic influences have been suppressed. The diagnosis of LPD in the clinical setting remains problematic and controversial primarily because there is no practical diagnostic method that has been validated. This article has reviewed the methods that have been used to diagnose LPD. BBT charts are insensitive; these charts reliably diagnose LPD only when there are persistent short luteal phases. There is disagreement whether ovarian follicular size, as determined by ultrasonography, is decreased in LPD; however, ultrasonographic diagnosis of LPD would require daily scans through ovulation, which makes this approach impractical. Mild hyperprolactinemia is a probable cause of LPD in a minority of patients; a physician should obtain a PRL level in LPD women with the realization that there is considerable sampling variability. Determination of serum gonadotropin levels (LH or FSH or both) is not practical for the clinical diagnosis of LPD. Random serum P levels, whether single or multiple, are not helpful in the diagnosis of LPD in individual patients. The secretory pattern of P results in such wide confidence limits that P samples from individuals cannot be compared to normal in a useful manner. Most of the controversy about the diagnosis of LPD has centered around the use of individual serum P levels. The timed endometrial biopsy relies on the endometrium as a bioassay of P over time. The endometrial biopsy has not been carefully validated in terms of its sensitivity or accuracy for the diagnosis of LPD. However, it remains the best current method for the diagnosis of LPD when the standard guidelines for its use are followed. As opposed to the other tests for LPD, awareness of the usefulness of the biopsy has increased as we have learned more about CL physiology. No current research method for the diagnosis of LPD appears to be a practical method that could be applied in the clinical setting. Specific secretory proteins from the endometrium and methods to measure hormone secretion that circumvent the secretory pattern hold promise for improved methods to diagnose LPD in the future.
Ovarian secretion of testosterone and androstenedione is increased in postmenopausal women with endometrial cancer, and insulin stimulates ovarian stromal androgen synthesis in vitro. We undertook this study to investigate whether women with endometrial cancer have increased serum immunoreactive insulin levels. Ten postmenopausal women with endometrial carcinoma and 10 postmenopausal women without cancer who matched the cancer patients in age, years since menopause, and percentage of ideal body weight were studied. The women with endometrial cancer had significantly higher fasting serum insulin levels than the normal women [mean, 187 +/- 26 (+/- SE) vs. 55 +/- 11 pmol/L; P less than 0.01]. The cancer patients had significantly higher insulin responses after glucose administration than normal women (sum of 1, 2, and 3 h postglucose values, 5545 +/- 1526 vs. 1444 +/- 156 pmol/L; P less than 0.02), even though their glucose responses were similar. Nests of luteinized cells, which were positive for testosterone by immunoperoxidase staining, were found in the ovarian stroma of 8 of the women with endometrial cancer, but in only 1 of those without cancer (P less than 0.01). Specific high affinity insulin receptors were demonstrable in the stroma of the postmenopausal ovaries. These results suggest that the frequency of stromal luteinization is increased in women with endometrial cancer and that insulin may play a role in the pathogenesis of this luteinization.
Research MethodologyBiomaterial CompatibilityGamete Handling Materials
Several popular and well-characterized polymeric materials were evaluated for their biocompatibility toward the cells unique to reproduction. To accomplish these studies, several in vitro tests were developed that evaluated biocompatibility between the polymers and spermatozoa, ova, and embryos. The data indicated significant differences between the materials with respect to their biocompatibility toward sperm motility, the sperm's ability to penetrate zona-free hamster eggs, and the ability of two-cell mouse embryos to divide. Polytetrafluoroethylene (PTFE-Teflon; PTFE, Chemplast Inc., Wayne, NJ), polyethylene glycol (PEG), and polyhydroxyethyl methacrylate (PHEMA) appear to be the most inert of the materials studied. Polyvinyl chloride (PVC; Tygon-Norton, Akron, OH) was found to be the most detrimental material toward gametes and embryos, with gross physiologic and morphologic changes observed in the PVC-exposed cells.
Fertility AwarenessPhysician Knowledge and AttitudesHealthcare Provider PerspectivesFamily Planning Counseling
A study of the knowledge, perceptions, and behavioral intentions of physicians regarding periodic abstinence (PA) methods was undertaken in Mauritius, Peru, the Philippines, and Sri Lanka. Most respondents considered PA to be useful, although even the PA providers prescribed mainly non-PA methods. Detailed knowledge of PA methods was not evident, but most physicians were willing to initiate general discussion about PA with patients. Physicians favored methods perceived as "scientific" and "modern," which primarily prevent pregnancy and secondarily avoid other health risks. When carefully presented as "scientific" and "modern," methods presented to medical audiences may find acceptance and be more likely to result in referral.
The ability of solutions of carboxymethylcellulose (CMC) and 32% dextran 70 to reduce postoperative adhesion formation was examined using a rabbit uterine-horn scrape model. Utilization of 50 mL of 32% dextran 70 did not reduce adhesion formation compared with control rabbits. However, intraperitoneal instillation of CMC significantly reduced postoperative adhesion formation. An inverse correlation was established between either the concentration of CMC employed (1%, 2%, and 3%) or the volume of 2% CMC employed (20, 30, 40, and 50 mL) and the extent of adhesion formation. It is concluded that in this animal model CMC, but not 32% dextran 70, was able to retard postoperative adhesion formation.
SurgeryTubal and Uterine PathologyClassificationClassification and Staging
To assess uterine activity before labor in patients delivering preterm, at term, and postterm, the maximum spontaneous contraction frequency per 10-minute window during the initial portion of antepartum fetal heart rate monitoring was analyzed. Patients with multiple gestation, third trimester bleeding, polyhydramnios, or premature rupture of membranes and those already diagnosed with preterm labor were eliminated from the study. Of the 2446 remaining patients (7247 antepartum fetal heart rate tests) who went into spontaneous labor, 237 did so before 37 completed weeks of gestation, 1077 entered labor at term (38 to 42 completed weeks), and 1132 did so after 42 weeks. There was a significant increase in maximum uterine activity per 10-minute window from 30 to 44 weeks of gestation (average 4.7% per week; r = 0.97, p less than 0.0001). When compared with patients delivering spontaneously at term, average maximum uterine activity per 10-minute window was greatest in the preterm labor group (p less than 0.05) and least in the postterm labor group (p less than 0.05). These differences were present for several weeks preceding the onset of spontaneous labor. All three groups showed a surge of uterine activity during the 3 days before the onset of spontaneous labor.