Origin of deoxycorticosterone sulfate (DOC-SO4) in plasma of pregnant women: pregnenolone-3,21-disulfate is a placental precursor of DOC-SO4.

The plasma levels of deoxycorticosterone sulfate (DOC-SO4) in near-term pregnant women are approximately 100 times those in plasma of men or non-pregnant women. Yet, neither the tissue site of synthesis nor the precursor of DOC-SO4 that enters maternal plasma is known. Several potential sources have been excluded: plasma DOC-SO4 is not derived from plasma DOC; and the secretion of C21-steroids (other than aldosterone) from the maternal adrenals during human pregnancy is not increased. Similarly, the transfer of DOC-SO4 from fetal plasma cannot account for the high level of DOC-SO4 in the maternal compartment, and a reduced clearance of plasma DOC-SO4 during pregnancy cannot account for the high levels of DOC-SO4. Indeed, the rate of clearance of DOC-SO4 from plasma is 10-100 times that of most other steroid sulfates. To address this question further, we evaluated the possibility that fetal plasma pregnenolone-3,21-disulfate serves as a precursor for DOC-SO4 formation in the placenta. The preferential hydrolysis of the 3beta-sulfate of pregnenolone-3,21-disulfate in placenta would give rise to pregnenolone-21-monosulfate, which, if acted upon by placental 3beta-hydroxysteroid dehydrogenase/delta5 --> 4 isomerase, could give DOC-SO4. [3H]Pregnenolone-3,21-disulfate was incubated with minces of human placental tissue for 5, 20, 60 and 120 min. Radiolabelled DOC-SO4, DOC, and pregnenolone-21-monosulfate were isolated from the incubation media and quantified. After a 5 min incubation, 7.5% of substrate was converted to DOC-SO4; and after 20, 60 and 120 min approximately 30% of the [3H]pregnenolone-3,21-disulfate was recovered from the media of these incubations as [3H]DOC-SO4. [3H]DOC was also present in the incubation media and the concentrations of this product increased as a function of incubation time. Therefore, pregnenolone-3,21-disulfate, which is present in very high concentrations in fetal plasma (approximately 1000 ng/ml), is metabolized in the placenta to DOC-SO4. Because of the fetal and maternal vascular arrangements of the hemochorioendothelial placenta of human pregnancy, steroids produced in syncytiotrophoblasts preferentially enter the intervillous space; thus, fetal plasma pregnenolone-3,21-disulfate may serve as a placental precursor of maternal plasma DOC-SO4.

Controlled ovarian hyperstimulation/intrauterine insemination cycles in subfertile couples. Effect of a six-day-only laboratory work week on cycle fecundity rates.

OBJECTIVE: Controlled ovarian hyperstimulation (COH) combined with intrauterine insemination (IUI) is commonly used to improve fecundability in subfertile couples with tubal patency. Daily hormonal and/or sonographic monitoring is considered important to minimize risks and determine optimal timing of human chorionic gonadotropin (hCG) administration. No patient monitoring or IUI services are available on Sundays in our program. We sought to determine if lack of Sunday monitoring and IUI services adversely affected cycle fecundity (CF) in our COH-IUI program. STUDY DESIGN: We retrospectively analyzed 1,336 consecutive COH-IUI cycles and compared the CF rate for IUIs performed on either Saturday or Monday (group I) with those done on Tuesday through Friday (group II). Cycles where IUIs would have been ideally scheduled on Sunday, as determined by the patient's estradiol level and/or ultrasound, were performed on either Saturday or Monday by altering the day of hCG administration. RESULTS: No difference existed in patient age, diagnosis, treatment or number of total motile sperm inseminated between groups I and II. The CF rate for group I (13.8%/cycle) was not significantly different than that for group II (11.8%). CONCLUSION: We were unable to demonstrate any significant effect on pregnancy rates of suboptimal hCG timing in COH-IUI cycles resulting from the lack of Sunday services.

Identification of hormonal parameters for successful systemic single-dose methotrexate therapy in ectopic pregnancy.

Single-dose methotrexate is an alternative to surgery in treating ectopic pregnancy. Because success rates vary, we sought to identify factors which predict treatment outcome. A total of 44 women with ectopic gestation were treated. The non-laparoscopic diagnosis of ectopic pregnancy was made following history, physical examination, ultrasound, endometrial biopsy and the measurement of serial beta-human chorionic gonadotrophin (HCG) and progesterone concentrations. Methotrexate (50 mg/m2 i.m.) was administered, with a second dose given 1 week later in patients with plateauing or rising beta-HCG concentrations. Of 44 patients, 23 (52.3%) were successfully treated with one dose. An additional 10 women (22.7%) were also successfully managed but required a second dose, giving an overall success rate of 75.0%. In all, 11 women (25.0%) required surgery, four of whom experienced tubal rupture. Receiver operator curves were constructed to optimally select pretreatment beta-HCG and progesterone cut-off concentrations for successful treatment. Using beta-HCG < 1500 IU/l or progesterone < 7.0 ng/ml (22.3 nmol/l) as a cut-off concentration produced a diagnostic test with a sensitivity of 87.5%, a specificity of 90.0%, a positive predictive value of 96.6% and a negative predictive value of 69.2%. Conversely, this model predicts that patients with serum beta-HCG concentrations > or = 1500 IU/l and progesterone concentrations > or = 7.0 ng/ml are at far greater risk of failing single-dose methotrexate therapy.

High-order oocyte transfer in gamete intrafallopian transfer patients 40 or more years of age.

OBJECTIVE: To analyze whether a policy of high-order oocyte transfer would be effective in women > or = 40 years of age who are undergoing GIFT, and further, whether a specific subgroup of these patients could be identified where clinical pregnancy was more likely to occur. DESIGN: Prospective descriptive study. SETTING: Patients in a university-based reproductive endocrinology and infertility practice. PATIENTS: Infertile women > or = 40 years of age who underwent GIFT cycles between January, 1990 and December, 1993 after not having achieved pregnancy with at least three previous cycles of superovulation and intrauterine insemination. INTERVENTIONS: Gamete intrafallopian transfer was performed after controlled ovarian hyperstimulation with hMGs. High-order oocyte transfer was employed. MAIN OUTCOME MEASURES: Clinical pregnancy rates (PRs). RESULTS: The overall clinical PR was 24.5% per retrieval (12/49) and 25.5% per transfer (12/47). A significantly higher number of oocytes were retrieved in patients who became pregnant than those who did not. Patient age, cycle day 3 FSH level, E2 level on the day of hCG administration, number of oocytes transferred, and total number of motile sperm transferred did not differ significantly between the two groups. The clinical PR per transfer was significantly higher in patients with more than five oocytes transferred (10/27, 37%) versus those with five or less oocytes transferred (2/20, 10%). No multiple gestations were obtained. CONCLUSION: The number of oocytes retrieved in women > or = 40 years of age undergoing GIFT is the main determinant predicting clinical pregnancy. High-order oocyte transfer seems to lead to a favorable PR while the risk of multiple gestation is limited.

Laparoscopic gonadectomy in complete androgen insensitivity syndrome.

Laparoscopic orchiectomy was performed in a 16-year-old patient with complete androgen insensitivity syndrome. Pathology revealed in situ carcinoma of the seminiferous tubules.

Serum progesterone as a predictor of methotrexate success in the treatment of ectopic pregnancy.

OBJECTIVE: To determine the prognostic value of a single serum progesterone measurement for resolution of ectopic pregnancy following methotrexate therapy. METHODS: All patients attending our infertility clinic had quantitative beta-hCG and serum progesterone measured prospectively within the first week of missed menses. Ectopic pregnancy was diagnosed nonsurgically by poorly rising beta-hCG levels and lack of evidence of intrauterine gestation by transvaginal sonography. Once diagnosed, candidates received a single intramuscular injection of methotrexate, 50 mg/m2. Treatment outcome was categorized as either resolved or requiring surgery, and interpreted with respect to serum progesterone measured within 24 hours of methotrexate administration. RESULTS: Twenty-one patients were treated for ectopic pregnancy. Eleven had serum progesterone levels greater than 10 ng/mL and ten patients had levels of 10 ng/mL or less. The two groups did not differ significantly with respect to age, weight, hCG at the time of methotrexate administration, or amount of methotrexate administered. Of the 11 patients with serum progesterone levels above 10 ng/mL, only five had pregnancies that resolved following methotrexate. All ten patients with levels less than 10 ng/mL had resolution. This difference is significant (P = .009, 95% confidence interval 0.26-0.84). There was no improvement in the prediction of outcome when either the absolute or daily percentage increase of hCG was determined before methotrexate administration. CONCLUSION: A single serum progesterone measurement above or below 10 ng/mL is useful for predicting resolution of tubal pregnancy with methotrexate treatment.

Tubal selection for gamete intrafallopian transfer.

When both fallopian tubes appear normal, tubal selection for GIFT is left to the surgeon's discretion. We were interested to learn whether pregnancy rates were influenced by the choice of tubal transfer in relation to ovarian dominance. Ovarian dominance was defined sonographically as the ovary containing the greater number of follicles having a mean diameter > 16 mm. In a retrospective analysis of 144 GIFT procedures, the clinical pregnancy rate for transfers performed to the tube ipsilateral to the dominant ovary was significantly higher than that of transfers made to the contralateral tube (0.414 versus 0.228, P = 0.042). This difference could not be attributed to either patient characteristics or cycle performance. We suggest that gamete transfer be performed ipsilateral to the side with the greater number of dominant follicles to optimize pregnancy rates.

The utility of a home urinary LH immunoassay in timing the postcoital test.

OBJECTIVE: To evaluate whether a urinary LH immunoassay improves timing of the postcoital test compared to traditional timing methods in normally ovulating women. METHODS: Subjects included 37 infertile couples evaluated in a tertiary care setting. A randomized, prospective trial was performed of two methods of postcoital test timing: urinary LH assay or the traditional timing by cycle-averaging and/or review of basal body temperature graphs. RESULTS: Similar serum estradiol, progesterone, LH, number of motile sperm per high-power field, cervical mucus scores, and postcoital test scores were identified in both groups. CONCLUSION: Urinary LH immunoassays do not appear to improve timing of the postcoital test as compared with traditional timing methods.

Gonadotropin-releasing hormone agonist in a GIFT program.

The authors describe their experience with the gamete intrafallopian transfer (GIFT) procedure in the treatment of infertility. Utilization of a gonadotropin-releasing hormone agonist resulted in a 51.9 percent clinical pregnancy rate and a low cancellation rate.

Use of urinary luteinizing hormone immunoassays in the assessment of luteal function in infertile women.

It has been suggested that the chronologic date of an endometrial biopsy performed to evaluate luteal adequacy should be based on the date of the luteinizing hormone surge rather than the date of the next menstrual period. Sixty-four infertile women used a urinary luteinizing hormone immunoassay to identify the luteinizing hormone surge; timed serum progesterone level tests and an endometrial biopsy were then performed. An out-of-phase endometrium was identified in 26.6% of cycles dated traditionally and 28.1% of cycles dated from the luteinizing hormone surge. No relationship was identified between progesterone levels and endometrial biopsy results when the next menstrual period was used. When the luteinizing hormone surge was used no progesterone cutoff value could be identified that would reliably distinguish between in-phase and out-of-phase cycles. Use of a urinary luteinizing hormone immunoassay offers no advantage over the next menstrual period and does not lead to better agreement between histologic and chronologic dating.

The role of superovulation with menotropins in ovulatory infertility: a review.

The risks of menotropin therapy (ovarian hyperstimulation syndrome, multiple gestation, adnexal torsion) are well known and have been previously described. Superovulation should not be considered for the indications described herein until more traditional therapies for infertility have been tried and found unsuccessful and sufficient time has elapsed for conception to occur. The cost of superovulation is high: the medications are expensive, frequent E2 monitoring and US studies are costly, and pregnancy complications relating to the higher rate of pregnancy loss and multiple gestation may add substantially to the overall cost. Yet, compared with IVF and GIFT, superovulation cycles combined with IUI cost between one third to one sixth that of an IVF cycle. Protocols involving combined CC/hMG/hCG, which reduce the total number of ampules of Pergonal needed per cycle and still provide multiple follicular development, may further reduce costs. There is a growing consensus that superovulation-IUI protocols should be attempted before GIFT and IVF in couples with normal pelvic viscera. There is little doubt that IVF and GIFT cycles are more costly, stressful, and complex. No comparative data have clearly shown IVF and GIFT to be superior to superovulation protocols in ovulatory women with normal pelvic anatomy. In the only study examining this issue published to date, Kaplan et al. retrospectively analyzed all GIFT and superovulation/IUI cycles at a single university center and found GIFT to be three times more efficient. However, the inherent limitations of a nonrandomized, nonprospective study of this kind are obvious as these authors have suggested. Therefore, it may be wise to consider the use of superovulation before assisted reproductive technologies until this issue is settled. It would be interesting to determine if the high PRs reported for couples with unexplained infertility or mild endometriosis in IVF and GIFT cycles in some centers not incorporating superovulation/IUI protocols would hold up if such an approach was routinely followed. Despite the increasing acceptance of superovulation protocols, we must be aware that many of the studies suggesting a role of hMG in treating ovulatory infertile women with normal pelvic anatomy suffer from deficiencies in experimental design. In a payor-driven system, such as in the United States, the difficulties in designing and carrying out scientifically sound clinical studies examining infertility therapies are obvious. The lack of federal or outside funding for the study of infertility issues contributes to the problem. It is our hope that better designed studies examining the role of superovulation in the treatment of ovulatory infertile women with normal pelvic anatomy will be forthcoming.

Adnexal torsion in menotropin-induced pregnancies.

Adnexal torsion of enlarged ovaries during early pregnancy is an infrequent but serious complication of menotropin therapy. Over 4 years, we encountered four cases of adnexal torsion among 648 menotropin-induced pregnancies. Multiple gestation may be a predisposing factor. The history of exogenous gonadotropin use, the acute clinical presentation, and the use of pelvic sonography facilitate the diagnosis. Although adnexectomy is well tolerated and pregnancy outcome is acceptable, future efforts should involve identifying preventive measures and more conservative means of therapy in these women.

Risk of a second consecutive first-trimester spontaneous abortion in women who conceive with menotropins.

It is generally recognized that a spontaneous abortion rate of approximately 25% exists in human menopausal gonadotropin/human chorionic gonadotropin (hMG/hCG)-induced pregnancies. Despite this, little is known regarding the prognosis of future menotropin-induced pregnancies in women who abort in their first hMG pregnancy. We retrospectively reviewed the obstetrical outcome of women who achieved two or more menotropin pregnancies between the years 1980 and 1987. Nineteen of 40 patients (48%) whose first hMG pregnancy ended in an early spontaneous abortion went on to abort in a second hMG pregnancy, as compared with only 1 of 15 women (6.7%) whose first hMG pregnancy was successful. Age, parity, weight, height, and plasma estradiol levels at hCG administration did not differ between the two groups. From this data we conclude that women whose first hMG pregnancy results in a spontaneous abortion are at high risk for another spontaneous abortion in a subsequent menotropin conception.

Home urinary luteinizing hormone immunoassays: clinical applications.

Home ovulation prediction kits represent a valuable advance in monoclonal antibody technology and offer patients a quick, reliable, and relatively inexpensive means to predict the day of ovulation. These kits are used widely by patients trying to conceive and are commonly recommended by physicians involved in the care of infertile couples. They provide a more accurate and practical means to prospectively predict the time of ovulation than do BBT graphs or cervical mucus exams, and can be used as presumptive evidence of ovulation. Whereas ovulation prediction kits appear to be most useful for couples in timing sexual intercourse, other possible uses exist, including timing of AI, the PCT, and the endometrial biopsy for luteal phase evaluation. Despite multiple potential applications, clinical studies which support the use of urinary LH immunoassays in the evaluation and treatment of the infertile couple are quite limited. More well-designed studies to define the clinical value of ovulation prediction kits need to be undertaken.