[Indications for in vitro fertilization: comparison of the Dutch guidelines with the published evidence]. / Indicaties voor in-vitrofertilisatie: vergelijking van de Nederlandse richtlijnen met de gepubliceerde onderzoeksresultaten.

The guideline 'Indications for in vitro fertilisation (IVF)' of the Dutch Society for Obstetrics and Gynaecology (Dutch acronym: NVOG) reports limited international evidence on this subject. A review of the published studies of effectiveness and cost-effectiveness shows that the possibilities to compare the studies and to translate the results to the diagnostic indications according to the Dutch guideline are indeed limited. This is due to differences in the study-populations, different outcome measures and differences in the severity of the underlying pathology. The results of foreign cost-effectiveness studies cannot easily be generalised to the Dutch situation due to differences in the consumption of medical care, the policy as to indications and the price-structure. For the indications inoperable tubal pathology and, to a lesser extent, severe male subfertility there is sufficient evidence-based support for the (cost-)effectiveness of IVF or intracytoplasmic sperm injection (ICSI) in comparison to waiting for spontaneous pregnancy to occur. There is insufficient current literature to support recommendations for the other causes of infertility as given in the Dutch guideline.

Non-invasive management of patients with suspected ectopic pregnancy: a survey among Dutch gynaecologists.

OBJECTIVE: To investigate if implementation of a non-invasive diagnostic work up of patients with suspected ectopic pregnancy, involving transvaginal sonography and serum human chorionic gonadotrophin (hCG) measurement decreases the likelihood of performing diagnostic laparoscopies. STUDY DESIGN: We interviewed 27 Dutch gynaecologists using 16 structured case summaries in a fractional factorial design. Each case summary concerned a hypothetical patient with suspected ectopic pregnancy. For each case presentation, the gynaecologists were asked for their inclination to perform laparoscopy. RESULTS: There were substantial differences in the degree to which data from a non-invasive work-up influenced the decision to perform a laparoscopy. Some gynaecologists would perform laparoscopy in all 16 patients at the first visit, whereas others would initially admit none of them. CONCLUSION: Dutch gynaecologists seem to be familiar with a non-invasive diagnostic approach in women with suspected ectopic pregnancy. However, there are considerable differences in management approach probably due to individual variability in weighing the risks and benefits of expectant management.

Are gestational age and endometrial thickness alternatives for serum human chorionic gonadotropin as criteria for the diagnosis of ectopic pregnancy?

OBJECTIVE: To compare gestational age and endometrial stripe thickness measurement with serum hCG measurement as criteria for the diagnosis of ectopic pregnancy (EP). DESIGN: Prospective study. SETTING: Two large teaching hospitals in Amsterdam, The Netherlands. PATIENT(S): Three hundred fifty-four consecutively seen pregnant patients who presented between September 1993 and April 1996 with suspected EP and in whom transvaginal ultrasonogram showed no intrauterine pregnancy or EP. Ultrasonography was performed by one of the study investigators or, during shifts, by the resident on call. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): The accuracy of gestational age, endometrial stripe thickness, and serum hCG measurement in the diagnosis of EP was evaluated with receiver operating characteristic curve analysis. RESULT(S): Gestational age and endometrial stripe thickness could not discriminate between patients with EP and patients without EP, whereas serum hCG had an acceptable area under the receiver operating characteristic curve. CONCLUSION(S): Gestational age and endometrial thickness are not useful in the diagnosis of EP. Serum hCG measurement is the diagnostic instrument of choice in patients with suspected EP when transvaginal ultrasonography does not reveal a diagnosis.

Treatment of tubal pregnancy in the netherlands: an economic comparison of systemic methotrexate administration and laparoscopic salpingostomy.

OBJECTIVE: This study was undertaken to compare from a societal perspective the costs of systemic methotrexate administration with those of laparoscopic salpingostomy for the treatment of patients with tubal pregnancy. STUDY DESIGN: An economic evaluation was set up in tandem with a multicenter randomized clinical trial that compared systemic methotrexate administration and laparoscopic salpingostomy for the treatment of 100 hemodynamically stable patients with laparoscopically confirmed unruptured tubal pregnancy. Data on resources used for treatment and lost production time were prospectively collected and costs of both treatments were calculated by multiplying actual expenses for resource units at a single center and resource unit use measured in all centers. Costs were originally calculated in Dutch guilders and converted to US dollars at a rate of 1.67 guilders/$1. RESULTS: Because clinical outcomes of the trial were equivalent for the 2 strategies a cost-minimization analysis was done. Mean total costs per patient were $5721 for systemic methotrexate administration and $4066 for laparoscopic salpingostomy, with a mean difference of $1655 (95% confidence interval, $906-$2414). Costs of systemic methotrexate administration were similar to those of salpingostomy for patients in whom the initial serum human chorionic gonadotropin concentration was <1500 IU/L, a cutoff value that had not been previously hypothesized. In a scenario without a confirmatory laparoscopy, in which transvaginal ultrasonography and serial repeated serum human chorionic gonadotropin measurements were assumed to be as accurate as laparoscopy, systemic methotrexate therapy would have reduced total cost by $1500 for a patient with an initial serum human chorionic gonadotropin concentration of <1500 IU/L. In such a scenario total costs would have been similar for a patient with an initial serum human chorionic gonadotropin concentration in the range of 1500 to 3000 IU/L, whereas systemic methotrexate administration would be more costly for a patient with an initial serum human chorionic gonadotropin concentration of >3000 IU/L. CONCLUSIONS: Although systemic methotrexate administration is safe and effective for the treatment of tubal pregnancy, it does not necessarily reduce costs. Systemic methotrexate therapy could reduce costs if administered to patients with low initial serum human chorionic gonadotropin concentrations without confirmatory laparoscopy.

Corticosteroids do not influence ovarian responsiveness to gonadotropins in patients with premature ovarian failure: a randomized, placebo-controlled trial.

OBJECTIVE: To determine the effect of corticosteroids on ovarian responsiveness to exogenous gonadotropins in patients with idiopathic premature ovarian failure (POF). DESIGN: Placebo-controlled, randomized, double-blind, multicenter study. SETTING: Two tertiary care academic centers for reproductive endocrinology and fertility and two general teaching hospitals. PATIENT(S): One hundred patients with idiopathic POF intended to enter the study. The study was discontinued after 36 patients failed to ovulate. INTERVENTION(S): Endocrine and immune parameters were tested on days 1 and 15. On day 1, subjects were randomized to receive either 9 mg of dexamethasone daily or placebo. From day 5 onward, 300 IU of hMG daily was added for 10 days in both groups. The dosage of dexamethasone was decreased stepwise in the second week and discontinued after day 15. Patients were monitored by transvaginal ultrasonography and by determining serum E2 levels. MAIN OUTCOME MEASURE(S): Ovulation rate. Fifty patients would have to be included in each study group to detect a statistically significant difference of 20% in the ovulation rate between the two groups with alpha = 0.05 and beta = 0.1 (one-tailed test). RESULT(S): No ovulation was recorded in the first 36 patients. Interim analysis showed that the 95% confidence intervals of an ovulation rate of 0 were 0-17% for the dexamethasone arm (n = 19) and 0-19% for the placebo arm (n = 17). Because the preset objective (a difference of 20%) would never be reached, the study was discontinued. CONCLUSION(S): Corticosteroids do not influence ovarian responsiveness to gonadotropins in patients with idiopathic POF.

Should patients who are suspected of having an ectopic pregnancy undergo physical examination?

OBJECTIVE: To determine whether physical examination is useful for patients with suspected ectopic pregnancy (EP) for whom transvaginal sonography is performed and serum hCG levels are measured. DESIGN: Prospective study. SETTING: Two large teaching hospitals. PATIENT(S): Three hundred eighty-two patients with suspected EP, based on a positive urine pregnancy test and the presence of abdominal pain, vaginal bleeding, or risk indicators. INTERVENTION(S): Abdominal examination, speculum inspection, and digital vaginal examination. MAIN OUTCOME MEASURE: A final diagnosis made by transvaginal sonography, serum hCG measurement, and, if necessary, confirmatory laparoscopy. RESULT(S): One hundred sixteen (30%) of the 382 patients had an EP. At external abdominal examination, rebound tenderness and muscular rigidity had likelihood ratios of 3.7 and 8.0, respectively. Findings at speculum inspection and digital vaginal examination had likelihood ratios between 0.33 and 2.4. Logistic regression analysis showed that the additional information provided by physical examination for the diagnosis of EP is limited compared with the information provided by transvaginal sonography and serum hCG measurement alone. CONCLUSION: On the basis of our results, we believe that vaginal digital examination for patients with suspected EP is unnecessary.

Can noninvasive diagnostic tools predict tubal rupture or active bleeding in patients with tubal pregnancy?

OBJECTIVE: To evaluate the ability of noninvasive diagnostic tools to predict tubal rupture and active bleeding in patients with tubal pregnancy. DESIGN: Prospective cohort study. SETTING: Two large teaching hospitals in Amsterdam, The Netherlands. PATIENT(S): Consecutively seen patients with suspected tubal pregnancy who were scheduled to undergo confirmative laparoscopy. MAIN OUTCOME MEASURE(S): Tubal rupture and/or active bleeding confirmed at laparoscopy. RESULT(S): Sixty-five (23%) of 288 patients had tubal rupture and/or active bleeding at laparoscopy. Abdominal pain, rebound tenderness on abdominal examination, fluid in the pouch of Douglas at transvaginal ultrasound examination, and a low serum hemoglobin level were independent predictors of tubal rupture and/or active bleeding. Pregnancy achieved with the use of IVF-ET and the presence of an ectopic gestational sac or an ectopic mass at ultrasound examination reduced the risk of tubal rupture. Abdominal pain was the most sensitive predictor, with a sensitivity of 95%. CONCLUSION(S): Because the nonsurgical management of tubal pregnancy should be used only when the risk of tubal rupture and/or active bleeding is low, it can be safely applied in only a limited number of patients.

Serum human chorionic gonadotropin measurement in the diagnosis of ectopic pregnancy when transvaginal sonography is inconclusive.

OBJECTIVE: To assess the accuracy of initial and repeated serum hCG measurements in the diagnosis of ectopic pregnancy (EP) in patients in whom transvaginal sonography is inconclusive and to evaluate whether patient characteristics influence the accuracy of serum hCG measurements. DESIGN: Prospective study. SETTING: Two large teaching hospitals in Amsterdam, the Netherlands. PATIENT(S): Three hundred fifty-four consecutively seen pregnant patients with suspected EP and inconclusive transvaginal sonographic findings. INTERVENTION(S): Serum hCG measurements. MAIN OUTCOME MEASURE(S): The performance of repeated serum hCG measurements in the diagnosis of EP was evaluated through the analysis of receiver operating characteristic curves. RESULT(S): Initial serum hCG measurements were more diagnostic in conjunction with sonographic evidence of an ectopic mass or fluid in the pouch of Douglas than in the absence of sonographic abnormalities. On repeated measurement, the course of the serum hCG concentration provided more diagnostic information than did the absolute serum hCG concentration 2 and 4 days after the start of the diagnostic process. CONCLUSION(S): The interpretation of serum hCG measurements should depend on additional findings at transvaginal sonography. A cutoff level of 1,500 IU/L is recommended for patients with an ectopic mass or fluid in the pouch of Douglas; in patients without these findings, the cutoff level should be at least 2,000 IU/L. Four days after the start of the diagnostic process, any rise in the serum hCG concentration makes the diagnosis of EP very likely.

A prospective, randomized, cross-over comparison of two methods of artificial insemination by donor on the incidence of conception: intracervical insemination by straw versus cervical cap.

In a prospective, randomized study of insemination with donor semen, intracervical insemination by straw was compared with insemination using a cervical cap with an intracervical reservoir. A total of 91 patients completed 486 treatment cycles. There were no significant differences in age, parity, indication for insemination by donor, or method of cycle monitoring between women who became pregnant and those who did not conceive with either insemination method. In 236 standard intracervical insemination cycles, 14 patients became pregnant (5.9% per cycle), whereas 38 patients conceived in 250 cervical cap cycles (15.2% per cycle). Both the crude pregnancy rates and the cumulative pregnancy rates calculated by the Kaplan-Meier life-table method were significantly different (chi(2)-test, P < 0.001, and log-rank test, P < 0.005 respectively). Pregnancy rates in artificial insemination with cryopreserved donor semen may be improved by the use of a cervical cap when compared to cervical insemination by straw. The use of the cervical cap may prolong the exposure of the spermatozoa to the cervical mucus and prevent the backflow of semen into the vagina.

Randomised trial of systemic methotrexate versus laparoscopic salpingostomy in tubal pregnancy.

BACKGROUND: Laparoscopic salpingostomy is a well-established treatment for patients with tubal pregnancy who desire to retain fertility. Another approach that preserves the fallopian tube is medical treatment. We compared systemic methotrexate and laparoscopic salpingostomy in the treatment of tubal pregnancy. Outcome measures were treatment success, tubal preservation, and homolateral tubal patency. METHODS: Between January, 1994, and September, 1996, haemodynamically stable patients with laparoscopically confirmed unruptured tubal pregnancy and no signs of active bleeding were randomly assigned systemic methotrexate (four 1.0 mg/kg doses of intramuscular methotrexate alternated with 0.1 mg/kg oral folinic acid) or laparoscopic salpingostomy. Treatment success was defined as complete elimination of the tubal pregnancy (serum human chorionic gonadotropin < 2 IU/L) and preservation of the tube. Homolateral tubal patency was assessed by hysterosalpingography. Analysis was by intention to treat. FINDINGS: 100 patients were included in the trial. Of 51 patients allocated systemic methotrexate, 42 (82%) were successfully treated with one course; two (4%) patients needed a second course for persistent trophoblast. Surgical intervention was needed in seven (14%) patients; salpingectomy was necessary in five of these patients for tubal rupture. Of the 49 patients allocated laparoscopic salpingostomy, 35 (72%) were successfully treated by laparoscopic salpingostomy alone; salpingectomy was needed in four (8%) patients, and ten (20%) needed methotrexate for persistent trophoblast. The tube was preserved in 46 (90%) patients in the methotrexate group versus 45 (92%) in the salpingostomy group (rate ratio 0.98 [95% CI 0.87-1.1]). Homolateral tubal patency could be assessed in 81 patients: the tube was patent in 23 (55%) of 42 patients in the methotrexate group and in 23 (59%) of 39 patients in the salpingostomy group (rate ratio 0.93 [0.64-1.4]). INTERPRETATION: In haemodynamically stable patients with unruptured tubal pregnancy, systemic methotrexate and laparoscopic salpingostomy were successful in treating the majority of cases. We found no significant difference between the treatments in the homolateral patency rate. Subsequent fertility outcome has to be awaited to show which treatment yields better fertility prospects.

Is conservative surgery for tubal pregnancy preferable to salpingectomy? An economic analysis.

OBJECTIVE: The traditional treatment of ectopic pregnancy is salpingectomy, while conservative surgery aims to save the function of the uterine tube. This study compares the effectiveness and the economic costs of salpingectomy and conservative tubal surgery in women with a tubal pregnancy. METHODS: Salpingectomy and conservative tubal surgery were compared economically, based on a combined retrospective and prospective cohort study and a review of the literature. A model was developed in which conservative surgery and salpingectomy with in vitro fertilisation and embryo-transfer (IVF-ET) were compared with salpingectomy alone. PARTICIPANTS: One hundred and fifteen consecutive women treated laparoscopically for tubal pregnancy. MAIN OUTCOME MEASURES: Complete removal of the tubal pregnancy; subsequent intrauterine pregnancy rate; economic analysis. RESULTS: Tubal pregnancy was always treated successfully by both methods, sometimes with additional treatment for persistent trophoblast. In the short term costs per patient were 1554 pounds (95% confidence interval [CI] 1501 pounds-1656 pounds) for salpingectomy and 1787 pounds (95% CI 1683 pounds-1930 pounds) for conservative surgery. The mean difference between costs of salpingectomy and costs of conservative surgery was 233 pounds (95% CI 80 pounds-371 pounds). Concerning subsequent intrauterine pregnancy, conservative surgery is slightly more effective than salpingectomy but is more expensive. Costs per subsequent intrauterine pregnancy are 4063 pounds. If IVF-ET is performed in all women who are not pregnant within three years after salpingectomy, costs per subsequent intrauterine pregnancy are 15,629 pounds. CONCLUSIONS: Salpingectomy is the treatment of choice in women not desiring future pregnancy. Salpingectomy seems less effective than conservative surgery when future pregnancy is desired, but is less costly. Conservative surgery seems more cost effective than salpingectomy with additional IVF-ET.

An economic evaluation of laparoscopy and open surgery in the treatment of tubal pregnancy.

BACKGROUND: Laparoscopy has generally replaced open surgery in the treatment of ectopic pregnancy. This study assesses the impact of the introduction of laparoscopy in the surgical treatment of tubal pregnancy on costs. METHODS: Consecutive patients undergoing primary surgery for tubal pregnancy between January 1992 and December 1995 were included in the study. Surgery was performed laparoscopically or by open surgery. Cost for each treatment was calculated by multiplying resources used with calculated resource unit prices. The analysis was stratified for radical and conservative surgery. RESULTS: Data of 255 patients were analysed. Tubal pregnancy was successfully treated in all patients. Costs per patient were US$ 3,490 for radical open surgery, US$ 1,872 for radical laparoscopic surgery, US$ 3420 for conservative open surgery and US$ 2,125 for conservative laparoscopic surgery. Differences in costs were caused by a decreased duration of hospital stay after laparoscopy, and, in case of conservative surgery, by an increased persistent trophoblast rate after laparoscopy. CONCLUSIONS: Laparoscopy is equally effective as open surgery in the treatment of tubal pregnancy, and considerably reduces costs.

Diagnosis of ectopic pregnancy after in vitro fertilization and embryo transfer.

OBJECTIVE: The combination of transvaginal sonography and serum hCG measurement is reliable in the diagnosis of ectopic pregnancy (EP) in spontaneous pregnancies. In patients who became pregnant through IVF-ET, transfer of multiple embryos after IVF could be responsible for the different performance of these tests. We evaluated the discriminative capacity of transvaginal sonography in combination with hCG measurement in the diagnosis of EP after IVF-ET. DESIGN: Prospective cohort study. SETTING AND PATIENT(S): Consecutive patients, pregnant through IVF-ET, who presented with clinically suspected EP. INTERVENTION(S): Transvaginal sonography, serum hCG measurement at 6, 9, and 15 days after ET and after a negative transvaginal sonography. MAIN OUTCOME MEASURE(S): Ectopic pregnancy confirmed at laparoscopy. RESULT(S): Between September 1993 and May 1996, 86 women were included in the study, of whom 24 had an EP. Transvaginal sonography identified 46 intrauterine pregnancies and 5 EPs, but serum hCG could not diagnose EPs in patients in whom transvaginal sonography did not show a gestational sac. Serum hCG measurement 9 days after ET could identify pregnancy failure with 100% specificity at a cut-off value of 18 IU/L, but it could not identify patients with EP with enough certainty to justify immediate treatment. CONCLUSION(S): We recommend single serum hCG measurement 9 days after ET to discriminate between viable and nonviable pregnancies. Transvaginal sonography can be postponed until 5 weeks after ET, except for patients with abdominal pain and/or vaginal bleeding, or patients with a serum hCG level of < 18 IU/L.

Serum human chorionic gonadotropin clearance curves in patients with interstitial pregnancy treated with systemic methotrexate.

OBJECTIVE: To evaluate short-term effectiveness of systemic methotrexate (MTX) in interstitial pregnancy. DESIGN: Case series. SETTING: Two Dutch teaching hospitals. PATIENT(S): Eight consecutive patients with an unruptured interstitial pregnancy. INTERVENTION(S): Four doses of 1.0 mg/kg IM MTX alternated with 0.1 mg/kg oral folinic acid. Serum hCG concentrations were determined before the first MTX injection and followed until levels were undetectable. A second MTX course was started on day 14, if by then serum hCG concentrations were > 40% of the initial value. Serum hCG clearance curves of all patients in the present study were compared with those from our earlier studies, in which a different folinic acid regimen (15 mg orally) was used. MAIN OUTCOME MEASURE(S): Serum hCG clearance curves. RESULT(S): All patients were treated successfully: five with one course and three with two courses. Serum hCG clearance curves of these patients tended to decline more rapidly than those successfully treated with the 15 mg folinic acid regimen. CONCLUSION(S): Systemic MTX is an attractive therapeutic option in the conservative treatment of unruptured interstitial pregnancy. The regimen of four doses of 1.0 mg/kg IM MTX alternated with 0.1 mg/kg folinic acid is effective. Serum hCG clearance curves may serve as a guideline for monitoring MTX treatment, thus enabling a timely detection of impending treatment failure.

Effects of ketoprofen and mesosalpinx infiltration on postoperative pain after laparoscopic sterilization.

OBJECTIVE: To determine whether preoperative ketoprofen and mesosalpinx infiltration, either alone or in combination, favorably influence postoperative recovery after outpatient laparoscopic sterilization. METHODS: In a double-blind, randomized, placebo-controlled study, 20 women received 100 mg of oral ketoprofen preoperatively, and each mesosalpinx was infiltrated with 5 mL of saline plus epinephrine 1:200,000; 20 women were given oral ketoprofen, and each mesosalpinx was infiltrated with 5 mL of bupivacaine 0.5% with epinephrine 1:200,000; and 20 women received a placebo capsule with mesosalpinx infiltration. Pain was assessed by a visual analogue scale and a self-assessment 11-point scale; outcome was assessed by discharge time, consumption of analgesics, incidence of nausea and vomiting, and the number of postoperative days to full recovery. RESULTS: Pain ratings in the ketoprofen-only group were significantly higher than in the two other groups (P < .001). Preoperative ketoprofen alone provided insufficient postoperative pain relief, necessitating the use of opiates and peripheral analgesics. Nausea and vomiting were highest in these subjects, as was intake of peripheral analgesics at home. Times to discharge were also the longest in this group (median 385 minutes, range 260-510) and differed significantly from both other groups (P < .001). It took 4-13 days to recover. In contrast, women with only a mesosalpinx block ambulated and recovered sooner, but times to discharge were still prolonged (median 240 minutes, range 105-375). Recovery usually occurred by the fourth postoperative day. The combination of preoperative ketoprofen and mesosalpinx block resulted in the shortest times to discharge (median 190 minutes, range 80-330), the least consumption of peripheral analgesics, and the lowest incidence of nausea and vomiting. Recovery occurred by the fourth postoperative day. CONCLUSION: Mesosalpinx infiltration has a favorable effect on postoperative recovery after day-surgery laparoscopic sterilization. Still better results can be obtained with a multimodal analgesic approach, combining mesosalpinx infiltration with preoperative ketoprofen.

Chlamydia trachomatis and ectopic pregnancy: retrospective analysis of salpingectomy specimens, endometrial biopsies, and cervical smears.

AIMS: To examine the role of Chlamydia trachomatis in ectopic pregnancy by detection of DNA in archival salpingectomy specimens, and in their preceding cervical specimens and endometrial biopsies, by using the polymerase chain reaction (PCR). METHODS: Archival paraffin embedded salpingectomy tissues (n = 48) from 37 women with ectopic pregnancy were examined for the presence of C trachomatis plasmid and omp1 DNA by PCR. In addition, preceding cervical specimens (n = 58) stored either as cervical cell suspensions or as archival cervical smears, and preceding endometrial biopsies (n = 18), taken 0-5.8 years before the ectopic pregnancy, were examined by PCR for the presence of C trachomatis. RESULTS: C trachomatis DNA was detected in only one of the 48 salpingectomy specimens from 37 women. However, in six of the 37 women, C trachomatis DNA was detected in the genital specimens (cervix and/or endometrial) taken before salpingectomy. C trachomatis infections were mostly found in endometrial or cervical specimens taken more than three years before ectopic pregnancy. No chlamydial DNA was found in endometrial or cervical specimens taken at the same time of the ectopic pregnancy. CONCLUSIONS: Although no C trachomatis DNA was found in salpingectomy specimens, several women with ectopic pregnancy had C trachomatis infections in endometrial and cervical specimens in the past. This suggests that at least in these cases the ectopic pregnancy is a late post-inflammatory complication of an ascending C trachomatis infection resulting in a scarred fallopian tube.

The response of the pituitary-ovarian axis to pulsatile administration of gonadotropin-releasing hormone in long-term oral contraceptive users.

OBJECTIVE: Our purpose was to differentiate between pituitary and hypothalamic feedback effects of oral contraceptives. STUDY DESIGN: Twenty micrograms of gonadotropin-releasing hormone was administered intravenously at 90-minute intervals for 4 days to 14 long-term users of a combined oral contraceptive (30 micrograms of ethinyl estradiol and 150 micrograms of levonorgestrel), starting at different moments in the pill cycle. On the fourth day of administration the pulsatile release of luteinizing hormone was determined by blood sampling every 10 minutes for 6 hours. The sensitivity of the pituitary was determined before, during, and after treatment with gonadotropin-releasing hormone by a 100 micrograms gonadotropin-releasing hormone challenge test. On each sampling day serum estradiol, progesterone, and prolactin levels were measured, and ovarian ultrasonography was performed. RESULTS: After 4 days of pulsatile gonadotropin-releasing hormone administration every exogenous gonadotropin-releasing hormone bolus was followed by an endogenous luteinizing hormone pulse of high amplitude (median 3.30 U/L). Both serum luteinizing hormone and follicle-stimulating hormone levels increased significantly (p < 0.001). The increase in follicle-stimulating hormone levels was accompanied by an increase in serum estradiol (p < 0.01). The luteinizing hormone response to a 100 micrograms bolus of gonadotropin-releasing hormone decreased during gonadotropin-releasing hormone treatment (p < 0.01), whereas the follicle-stimulating hormone response did not change. CONCLUSION: Pituitary sensitivity is not impaired during oral contraceptive use, suggesting that oral contraceptives exert their negative feedback effects predominantly at the hypothalamic level.