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OBJECTIVES: To determine the extent of contamination of ovarian follicular fluid and serum samples in women undergoing in-vitro fertilization and to study the effect of the contaminants on reproductive outcome. DESIGN: Inception cohort study. PATIENTS: Seventy-four women undergoing in-vitro fertilization at three regional clinics in Halifax, Hamilton, Ont., and Vancouver. MAIN OUTCOME MEASURES: Follicular fluid and serum levels of contaminants, cleavage rates and time to cleavage of first egg. RESULTS: Five chlorinated organic chemicals were frequently found in the two types of samples: alpha-chlordane (ALCH), dichlorochlorophenylethylene (DDE), heptachloroepoxide-oxychlordane (OXCH), hexachlorobenzene (HCB) and polychlorinated biphenyl (PCB). The levels were generally low. Regional differences between the three clinics were present. Samples from the Halifax clinic had the lowest frequency and level of contamination. The source of drinking water (well, bottled or municipal) was an important confounder. The concentrations of the five contaminants did not affect the cleavage rate or the time to cleavage of the first egg. CONCLUSION: Trace amounts of toxic and persistent chlorinated organic chemicals found in the follicular fluid of Canadian women undergoing in-vitro fertilization did not seem to have any adverse biologic effect on the rate of fertilization and the time to cleavage. Reasons for regional differences in the concentrations of contaminants require further study.

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In an attempt to evaluate the efficacy of salpingoovariolysis we studied 147 women who were found to have periadnexal adhesions on laparoscopic examination. Among these women, 69 were treated by laparotomy and salpingoovariolysis and 78 were not treated. There was no significant difference between the degree of adhesions in the treated group and in the nontreated group. With the use of life table analysis, the cumulative pregnancy rate at 12 and 24 months follow-up was 32% and 45% in the treated group and 11% and 16% in the nontreated group, respectively (p less than 10(-6)). We suggest that although pregnancy might occur in infertile women who have periadnexal adhesions, treatment with salpingoovariolysis is associated with a higher pregnancy rate.

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A double-blind, randomized, prospective therapeutic trial was conducted in 148 couples with unexplained infertility. Treatment consisted of 4 consecutive months of placebo or clomiphene citrate (CC) (100 mg) by mouth on cycle days 5 to 9, and placebo or human chorionic gonadotropin (hCG) (5,000 IU) intramuscularly on cycle days 19, 22, 25, and 28. There were 14 pregnancies during the trial and 39 pregnancies during observation before and after the trial. Placebo treatment resulted in no pregnancies over 4 months. Clomiphene citrate was significantly better than placebo (P less than 0.04), with a pregnancy rate of 19% over the course of 4 months. The pregnancy rate with hCG either alone (11%) or in combination with CC (7.6%), was not significantly better than placebo. Treatment-independent pregnancies, defined as those before treatment (but after enrollment), or more than 1 month after therapy, occurred in 16% of the couples, with a mean time to conception of 8.8 months. As part of their follow-up, 39 of the study couples subsequently underwent in vitro fertilization (IVF), and 43% were found to have a previously unrecognized male factor or fertilization defect. A pregnancy rate of 16% was achieved after a mean of 1.1 cycles in these 39 couples. The authors conclude that CC is useful in treating unexplained infertility and is a reasonable initial therapy. For couples who fail to conceive, IVF may be diagnostic as well as therapeutic.

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This study draws on decision analysis to estimate the utility of seminal variables in predicting pregnancy. The infertile couples selected (n = 709) excluded those who had donor insemination or known female factors (history of pelvic infection, ovulatory disorders, endometriosis, and tubal disease). Diagnostic test properties were calculated with respect to pregnancy for two variables derived from the semen analysis report: sperm density, and the total number of motile sperm in the ejaculate (TMS). Receiver-operating characteristic (ROC) curves based on sensitivity and specificity revealed that none of the proposed thresholds for sperm density or TMS is clearly a best choice. The highest positive predictive values for sperm density (75%) and TMS (75%) were associated with cutoff points at five million sperm per milliliter and five million motile sperm per ejaculate, respectively. The false positive rates when these cutoff points were used were 4.3% (sperm density) and 5.6% (TMS). ROC analysis provides visual and numeric evidence of the quality of a diagnostic test and constitutes a set of procedures for incorporating information from new tests of male gamete function into the diagnostic assessment of infertility.

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Among the male partners of 1074 infertile couples the mean results of semen analysis were sperm count 78 X 10(6)/ml, seminal volume 4.0 ml, proportion of progressively motile sperm 54%, proportion of sperm with normal morphologic features 81.4% and total motile sperm count 152.3 X 10(6) per ejaculate. After excluding 65 couples who chose donor insemination and 300 with known female causes of infertility, the cumulative pregnancy rates in the remaining 709 couples were higher with increasing sperm density and motility and seminal volume, but the higher rates were significant only when these variables were combined into total motile sperm count per ejaculate. The cumulative pregnancy rates were 20% with a total motile sperm count of 9 X 10(6) or less, 37% with a count of 10 to 19 X 10(6) and 52% with a count of 20 X 10(6) or more (p = 0.001). Counts higher than 20 X 10(6) were not associated with a further improvement in pregnancy rates, but variability in the results was high, which suggests that the test should be repeated as necessary to determine the true range. Although standards for these and other seminal variables are ill defined, the total motile sperm count incorporates the most useful prognostic information from semen analysis, and the associated pregnancy rates can help guide clinical decisions.

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To determine the reason for the higher pregnancy rate in couples with secondary infertility, the authors compared 237 infertile couples who had a previous pregnancy in the current partnership (secondary infertility) with 135 infertile couples in whom the woman had been pregnant only in a previous partnership and 925 couples with primary infertility. Couples with secondary infertility had the highest proportion of ovulation disorders (36%); these couples with secondary infertility and an ovulation disorder had the shortest duration of infertility (26 months). Cumulative pregnancy rates at 36 months were 56% in secondary fertility, 44% in primary infertility, and 42% in pregnancy in a previous partnership (P = 0.001). In this study, the better prognosis in secondary infertility may be related to the higher proportion of couples with ovulation disorders, who had a shorter duration of infertility. Abortion rates in the earlier pregnancies with current or previous partners were 37% and 30%, respectively; after the period of infertility, the abortion rates were 14% and 12%, respectively.

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The effect of androgens on the conversion of estradiol (E2) and estrone (E1) from estrone-3-sulfate (E1-S) was studied in explants of normal human term placentas. Explants incubated in medium supplemented with 2.0 microM E1-S showed that 50 microM dihydrotestosterone (DHT) stimulated E2 production 15-fold above control values after 0.5h, but neither 50 microM methyltestosterone (MT) nor 50 microM diethylstilbestrol (DES) had any effect. HCG (5.0 i.u./ml), alone or in combination with one of the androgens, did not influence the E2 production. When the explants were incubated in medium with 0.25 microM E1-S (the average concentration reported for late pregnancy plasma), DHT (0.5-50 microM) caused a dose- and time-dependent increase in E2 production, while E1 production and the combined accumulation of E2 and E1 were slightly inhibited by all doses of DHT during the 0.5-4h incubation. When E1 (0.1 microM) was used as substrate, DHT caused a dramatic dose- and time-dependent shift in the E1-E2 equilibrium towards E2. The results indicate that during late pregnancy, a particular class of androgens may increase the production of the more bioactive E2 from the circulating E1-S; the mode of action may be an enhanced conversion of E1 to E2.

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Late follicular phase postcoital tests in 355 infertile couples (selected to exclude severe defects in ovulation, seminal or tubal function) were scored for mucus characteristics and sperm motility. Cervical mucus characteristics were associated with postcoital sperm motility (P less than 0.001) but not with pregnancy. Postcoital sperm motility in cervical mucus was strongly associated with total motile sperm count per ejaculate (F = 5.38, P less than 0.001). Postcoital sperm motility was a weak predictor of pregnancy when more than five motile sperm were observed per high power microscopic field. When the log rank tests for postcoital sperm motility were repeated in groups with low (less than 10 million) and high (10 million or more) total motile sperm count per ejaculate, the association between postcoital sperm motility and pregnancy was not statistically significant. Regression analysis controlling for other potential predictors revealed no independent association between postcoital sperm motility and the later occurrence of pregnancy in this group of infertile couples.

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Evaluated were methods of ordering the many possible predictors of infertility outcome. The clinical characteristics of infertile couples were studied with respect to the occurrence of pregnancy during follow-up, by means of the methods of survival analysis. Among 1,297 couples who were infertile for 12 months or more, the cumulative pregnancy rate at 36 months with 95% confidence limits was 49% +/- 4%. The proportional hazards analysis identified three independent predictors of the occurrence of pregnancy from the couple's history (with P values in brackets): a history of pregnancy in the partnership (0.0001); shorter duration of infertility (0.0001); and shorter length of marriage (0.005). The predictors arising from the diagnostic process (with P values in brackets) were: fewer infertility diagnoses (0.0001); a favorable primary clinical diagnosis (0.001); and the presence of any tubal disease, regardless of the primary clinical diagnosis (0.001). The analysis selected an economical set of significant predictor variables and demonstrated that a longer period of contraception was associated with a lower pregnancy rate among infertile couples. Also, three simple questions from the history were nearly equivalent to the entire diagnostic process as predictors of the outcome.

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In a follow-up study of 1297 couples registered at a Nova Scotia infertility clinic with a complaint of infertility of at least 12 months' duration, the cumulative pregnancy rate at 36 months, with 95% confidence limits, was found to be 49 +/- 4%. The predictors of pregnancy by univariate analysis were a favourable primary clinical diagnosis (p less than 0.001), a duration of infertility of less than 3 years (p less than 0.001), a single diagnosis for the infertility (p less than 0.001), a previous pregnancy in the partnership (p = 0.001) and a length of marriage of less than 4 years (p = 0.002). Proportional hazards analysis confirmed these variables as predictors of pregnancy. The highest cumulative pregnancy rates after 12 and 36 months of follow-up were observed in cases of ovulation deficiency, and the lowest were seen in cases of tubal defects. However, before the process of diagnosing infertility begins, useful prognostic information can be determined from the length of marriage, the duration of infertility and the partnership's history of previous pregnancy.

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A combination of 1.0 mg dl-norgestrel and 0.1 mg ethinylestradiol was administered orally at 18 hours after the detection of luteinizing hormone rise and again at 30 hours in five healthy volunteers with normal menstrual cycles. The effects on ovarian function were studied by comparing the daily serum levels of progesterone (P), 17 alpha-hydroxyprogesterone, and estradiol (E2) measured in a control (placebo) cycle with those in two consecutive treatment cycles. Treatment did not alter the steroid levels in one subject. P was suppressed in one or both treatment cycles of four subjects. E2 was suppressed in both treatment cycles of one subject and produced widely fluctuating patterns in another. The hormonal patterns in the two consecutive treatment cycles of the same individual were similar in all but one instance, where only the P level in the second treatment cycle was diminished. These results showed that this treatment can elicit steroidogenic responses of varying degrees and duration. The contraceptive action may lie in the altered P and/or E2 level at certain points in the menstrual cycle.

PIP: A combination of 1.0 mg dl-norgestrel and 0.1 mg ethinyl estradiol was administered orally at 18 hours after detection of luteinizing hormone and again at 30 hours in 5 healthy volunteers with normal menstrual cycles. The effects on ovarian function were studied by comparing the daily serum levels of progesterone (P), 17alpha-hydroxyprogesterone, and estradiol (E2) measured in a control (placebo) cycle with those in 2 consecutive treatment cycles. Treatment did not alter the steroid levels in 1 subject. P was suppressed in 1 or both treatment cycles of 4 subjects. E2 was suppressed in both treatment cycles of 1 subject and produced widely fluctuating patterns in another. The hormonal patterns in the 2 consecutive treatment cycles of the same individual were similar in all but 1 instance, where only the P level in the 2nd treatment cycle was diminished. These results showed that this treatment can elicit steroidogenic responses of varying degrees and duration. The contraceptive action may lie in the altered P and/or E2 level at certain points in the menstrual cycle.

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We analyzed a two- to seven-year follow-up of 1145 infertile couples to determine the frequency of pregnancy occurring independently of treatment. Pregnancy occurred in 246 of 597 treated couples (41 per cent) and in 191 of 548 untreated couples (35 per cent). Thirty-one per cent of the pregnancies in treated couples occurred more than 3 months after the last medical treatment or more than 12 months after adnexal surgery. These pregnancies plus the 191 pregnancies in untreated couples constituted the category of "treatment-independent pregnancies" and accounted for 61 per cent of all pregnancies; for 44 per cent of those among couples with ovulation deficiency; for 61 per cent of those in couples with endometriosis, tubal defects, or seminal deficiencies; and for 96 per cent of those in couples with cervical factors or idiopathic infertility. We conclude that the potential for a spontaneous cure of infertility is high, that treatment for many classes of infertility should be evaluated by randomized clinical trials, and that in such trials random assignment of subjects to untreated control groups would be ethically acceptable.

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A combination of 1.0 mg dl-norgestrel and 0.1 mg ethinylestradiol (EE) was administered orally at 36 hours after the detection of the luteinizing hormone peak and again at 48 hours in 12 healthy volunteers with normal menstrual cycles. The effects on ovarian function were studied by comparing the daily serum levels of progesterone (P), 17 alpha-hydroxyprogesterone, and estradiol (E2) in control (placebo) and treatment cycles. Five subjects showed no significant change in the levels of these steroids but had a shortened luteal phase. The treatment significantly decreased both P and E2 levels in three subjects, while two subjects showed diminished E2 levels only. The remaining two subjects had lower P levels and fluctuating E2 patterns. Endometrial biopsies from both study cycles indicated asynchronous development of the epithelial and stromal components in the treatment cycle. These findings (abnormal luteal phase steroid levels and duration and outphased endometrial development) indicate that corpus luteum function was variously affected by the action of norgestrel-EE treatment.

PIP: A combination of 1.0 mg dl-norgestrel and 0.1 mg ethinyl estradiol (EE) was administered orally at 36 hours after detection of the luteinizing hormone peak and again at 48 hours in 12 healthy volunteers with normal menstrual cycles. The effects on ovarian functions were studied by comparing the daily serum levels of progesterone (P), 17alpha-hydroxyprogesterone, and estradiol (E2) in control (placebo) and treatment cycles. 5 subjects showed no significant changes in the levels of these steroids but had a shortened luteal phase. The treatment significantly decreased both P and E2 levels in 3 subjects, while 2 subjects showed diminished E2 levels only. The remaining 2 subjects had lower P levels and fluctuating E2 patterns. Endometrial biopsies from both study cycles indicated asynchronous development of the epithelial and stromal components in the treatment cycle. These findings (abnormal luteal phase steroid levels and duration and outphased endometrial development) indicate that corpus luteum function was variously affected by the action of norgestrel-EE treatment.

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Possible mechanisms of action of a combination of ethinylestradiol (EE) and dl-norgestrel as a postcoital contraceptive agent were studied in 12 healthy female volunteers. An oral dose of 0.1 mg of EE and 1.0 mg of dl-norgestrel was given at the predicted time of ovulation and again 12 hours later. Serum luteinizing hormone, prolactin, progesterone, 17 alpha-hydroxyprogesterone, and estradiol were measured by specific radioimmunoassays in blood samples obtained daily from the 8th day of the menstrual cycle to the 1st day of menses. Hormone profiles suggested that the medication elicited a range of individual variations in pituitary and/or ovarian responses. Histologic examination of the endometrium consistently showed significant alteration in endometrial development with a dissociation in maturation of glandular and stomal components. This postcoital contraceptive acts either by (1) suppressing ovulation or (2) disrupting luteal function by acting directly on the corpus luteum or by interfering with appropriate endometrial responses to ovarian steroids.

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Blood was obtained at various stages of the menstrual cycle from 201 women fitted with intra-uterine contraceptive devices (IUDs), and plasma levels of hCG were determined by radioimmunoassay. Urine samples were obtained from 117 of these women and tested, before and after sephadex gel filtration, in a haemagglutination inhibition test for pregnancy (Pregnosticon). Plasma hCG was undetectable (less than 25 MLU/ml) in all but one of the 201 women and, in this instance, the hCG-assay appeared to be measuring a midcycle peak of LH, as evidenced by high plasma FSH levels. All unextracted urines gave negative results in the Pregnosticon test but, after extraction, 18 of the 117 urines gave positive reactions, most of these being from women at midcycle or in the luteal phase. We conclude that the IUD does not permit the development of the embryo to a point where it is capable of secreting measurable amounts of hCG. Recent claims to the contrary are probably due to cross-reaction of LH or non-specific interference in the assays used for measuring hCG.

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