Follicle stimulating hormone versus clomiphene citrate in intrauterine insemination for unexplained subfertility: a randomized controlled trial.

STUDY QUESTION: Is FSH or clomiphene citrate (CC) the most effective stimulation regimen in terms of ongoing pregnancies in couples with unexplained subfertility undergoing IUI with adherence to strict cancellation criteria as a measure to reduce the number of multiple pregnancies? SUMMARY ANSWER: In IUI with adherence to strict cancellation criteria, ovarian stimulation with FSH is not superior to CC in terms of the cumulative ongoing pregnancy rate, and yields a similar, low multiple pregnancy rate. WHAT IS ALREADY KNOWN: FSH has been shown to result in higher pregnancy rates compared to CC, but at the cost of high multiple pregnancy rates. To reduce the risk of multiple pregnancy, new ovarian stimulation regimens have been suggested, these include strict cancellation criteria to limit the number of dominant follicles per cycle i.e. withholding insemination when more than three dominant follicles develop. With such a strategy, it is unclear whether the ovarian stimulation should be done with FSH or with CC. STUDY DESIGN, SIZE, DURATION: We performed an open-label multicenter randomized superiority controlled trial in the Netherlands (NTR 4057). PARTICIPANTS/MATERIALS, SETTING, METHODS: We randomized couples diagnosed with unexplained subfertility and scheduled for a maximum of four cycles of IUI with ovarian stimulation with 75 IU FSH or 100 mg CC. Cycles were cancelled when more then three dominant follicles developed. The primary outcome was cumulative ongoing pregnancy rate. Multiple pregnancy was a secondary outcome. We analysed the data on intention to treat basis. We calculated relative risks and absolute risk difference with 95% CI. MAIN RESULTS AND THE ROLE OF CHANCE: Between July 2013 and March 2016, we allocated 369 women to ovarian stimulation with FSH and 369 women to ovarian stimulation with CC. A total of 113 women (31%) had an ongoing pregnancy following ovarian stimulation with FSH and 97 women (26%) had an ongoing pregnancy following ovarian stimulation with CC (RR = 1.16, 95% CI: 0.93-1.47, ARD = 0.04, 95% CI: -0.02 to 0.11). Five women (1.4%) had a multiple pregnancy following ovarian stimulation with FSH and eight women (2.2%) had a multiple pregnancy following ovarian stimulation with CC (RR = 0.63, 95% CI: 0.21-1.89, ARD = -0.01, 95% CI: -0.03 to 0.01). LIMITATIONS, REASONS FOR CAUTION: We were not able to blind this study due to the nature of the interventions. We consider it unlikely that this has introduced performance bias, since pregnancy outcomes are objective outcome measures. WIDER IMPLICATIONS OF THE FINDINGS: We revealed that adherence to strict cancellation criteria is a successful solution to reduce the number of multiple pregnancies in IUI. To decide whether ovarian stimulation with FSH or with CC should be the regimen of choice, costs and patients' preferences should be taken into account. STUDY FUNDING/COMPETING INTEREST(S): This trial received funding from the Dutch Organization for Health Research and Development (ZonMw). Prof. Dr B.W.J. Mol is supported by a NHMRC Practitioner Fellowship (GNT1082548). B.W.M. reports consultancy for Merck, ObsEva and Guerbet. The other authors declare that they have no competing interests. TRIAL REGISTRATION NUMBER: Nederlands Trial Register NTR4057. TRIAL REGISTRATION DATE: 1 July 2013. DATE OF FIRST PATIENT'S ENROLMENT: The first patient was randomized at 27 August 2013.

Twin reduction by PGF2α intraluteal instillation in dairy cows.

The objective of this study was to determine whether induced luteolysis of one of the two corpora lutea in twin pregnancies would provoke spontaneous twin reduction. In Experiment 1, 12 post-partum cows with two corpora lutea in the same ovary were assigned to (three cows per group): Group I, Group II, Group III or Group IV receiving into one of the corpora lutea puncture with no treatment, 0.5 mg dinoprost, 1.5 mg dinoprost and 2.5 mg dinoprost, respectively. One of the two corpora lutea showed clear signs of luteolysis on Day 2 and was practically non-detectable on Day 7 after treatment in the three cows of the Group IV. In Experiment 2, 11 cows carrying live twins with two corpora lutea on Day 28 of gestation, eight bilateral and three unilateral, received 2.5 mg dinoprost into one of the corpora lutea. Corpus luteum reduction and embryo reduction after treatment were registered in 10 and 9 cows, respectively. In bilateral twin pregnancies, four cows suffering embryo reduction remained pregnant. In unilateral twin pregnancies, membrane detachment resulted in the death of both cotwins. In conclusion, although observations were based on few animals, there seems to be a mechanism that operates locally to transfer ovarian progesterone to the uterus, and also a quantitative relationship between the amount of progesterone secreted and support of conceptuses, resulting in death of one twin embryonic vesicle when one corpus luteum regresses.

Number of Intermediate Follicles. An Independent Risk Factor of Multiple Pregnancies in Intrauterine Insemination Cycles with Recombinant Follicle-Stimulating Hormone.

OBJECTIVE: To identify risk factors for multiple pregnancies in intrauterine insemination (IUI) cycles with recombinant follicle-stimulating hormone (r-FSH). STUDY DESIGN: A retrospective study including 205 IUI cycles with r-FSH which led to clinical pregnancies was conducted. A total of 145, singleton pregnancies and 60 multiple pregnancies were compared according to clinical characteristics and parameters of ovarian stimulation and IUI procedure. The relationships between size and number of follicles and serum estradiol (E2) levels and the risk of multiple pregnancies were investigated using multiple logistic regression analyses. RESULTS: The means of infertility length, serum E2 levels, the number of follicles 10 mm, 12 mm, and ≥ 16 mm, and the number of intermediate follicles (from 12 to ≤ 15 mm) at the day of ovulation triggering were significantly higher in the multiple pregnancy group as compared to in the singleton pregnancy group (p < 0.05). We first demonstrated that high E2 levels (≥ 1,000 pg/nL) and the number of intermediate follicles represent 2 independent and significant risk factors for multiple gestation in IUI cycles that used ovarian stimulation by r-FSH (p = 0.002 and p = 0.007, respectively). CONCLUSION: This study shows that high E2 levels and the number of intermediate follicles, independently of large follicles, can predict an increased risk of multiple pregnancy in r-FSH IUI cycles.

Positive effects of melatonin treatment on the reproductive performance of young border leicester rams mated to merino ewes in spring: preliminary observations.

Poor reproductive performance of Merino ewe flocks when mated to Border Leicester rams during spring may be due to seasonality of the Border Leicester breed. Two approaches were taken to test this assumption. Six young (12 months old) or six mixed-age (12, 24 and ≥36 months old) Border Leicester rams were either treated or not treated with melatonin implants (2 × 2 design) 6 weeks before the four groups of rams were each put with approximately 300 Merino ewes for an 8-week mating period. Implants were inserted in early September (experiment 1). The second approach was to yard or not yard ewes and mixed-age rams on several occasions during the first 3 weeks of the mating period (experiment 2). Pregnancy rate and twinning percentage were assessed by ultrasonography. In experiment 1, melatonin treatment in young rams increased (p < 0.001) pregnancy rate from 5.0% to 92.6%, but mixed-age rams did not respond (90.7% vs 89.5% for melatonin and non-melatonin treatments, respectively). Twinning rate was similar (p > 0.05) for ewes mated to either melatonin or non-melatonin-treated young rams (36.8% vs 40.0%, respectively), whereas melatonin significantly improved (p < 0.05) twinning rate in those ewes mated to mixed-age rams (49.1% vs 36.1%). After 6 weeks of melatonin treatment, scrotal circumference was greater (p < 0.05) in both young and mixed-aged rams than in untreated counterparts. In experiment 2, yarding of ewes and rams overnight on several occasions early in the mating period reduced (p < 0.001) pregnancy rate compared with non-yarded counterparts (89.5% vs 65.5%). Twinning rate was not affected (37.7% vs 36.1%, respectively). In summary, melatonin treatment of Border Leicester rams significantly improved flock reproductive performance in spring due to improved pregnancy rates with young rams and improved litter size with mixed-age rams.

Use of progestogens in pregnant and infertile patients.

Progesterone is an essential hormone in the occurence and maintenance of pregnancy. Natural or synthetic progestogens are commonly used in pregnant patients or patients undergoing infertility treatments for various indications. Most frequently put indications for the use of progestogens in these patient populations are the prevention of spontaneous preterm birth, the prevention of pregnancy loss in pregnancies with an unexplained recurrent pregnancy loss and in patients with threatened abortion. It is also used in pregnant women undergoing nonobstetric surgery, for infertility or recurrent pregnancy loss that is thought to be due to luteal phase defect or as a luteal support in stimulated IVF cycles. We aimed to review the current evidence for the use of progestogens in each of these settings.

Micronutrients in Multiple Pregnancies-The Knowns and Unknowns: A Systematic Review.

Maternal diet and nutritional status are of key importance with regard to the short- and long-term health outcomes of both the mother and the fetus. Multiple pregnancies are a special phenomenon in the context of nutrition. The presence of more than one fetus may lead to increased metabolic requirements and a faster depletion of maternal macro- and micro- nutrient reserves than in a singleton pregnancy. The aim of this systematic review was to gather available knowledge on the supply and needs of mothers with multiple pregnancies in terms of micronutrients and the epidemiology of deficiencies in that population. It was constructed in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses Statement (PRISMA). The authors conducted a systematic literature search with the use of three databases: PubMed/MEDLINE, Scopus and Embase. The last search was run on the 18 October 2020 and identified 1379 articles. Finally, 12 articles and 1 series of publications met the inclusion criteria. Based on the retrieved studies, it may be concluded that women with multiple pregnancies might be at risk of vitamin D and iron deficiencies. With regard to other microelements, the evidence is either inconsistent, scarce or absent. Further in-depth prospective and population studies are necessary to determine if nutritional recommendations addressed to pregnant women require adjustments in cases of multiple gestations.

Luteal activity following follicular drainage of subordinate follicles for twin pregnancy prevention in bi-ovular dairy cows.

Twin pregnancy is undesirable in dairy cattle. This study examines luteal activity following ultrasound-guided puncture and drainage of the smaller pre-ovulatory follicle at timed AI in cows with a pre-ovulatory follicle in each ovary. Luteal activity was determined through Doppler ultrasonography and plasma progesterone (P4) concentrations. The effects of GnRH treatment on Day 7 post-AI on subsequent luteal activity were also assessed. Two study groups were established: a control group of 29 cows and a follicular drainage (FD) group of 28 cows. After drainage, all cows developed a corpus luteum (CL) in the drained ovary. On Day 21 post-AI, drainage-induced CL and fellow CL were similar in terms of size and vascularization. According to a GLM repeated measures analysis of variance (P < 0.001), non-treated drained cows had lower P4 concentrations on Day 21 post-AI than non-treated non-drained cows, whereas GnRH treated cows, both drained and non-drained, showed the highest P4 concentrations at this time point. Twin pregnancy was recorded in 3 of the 8 pregnant control cows, whereas no twins were observed in the FD group. Our results indicate that luteal structures following follicular drainage were functional. As for the presence of an additional CL, this could suggest a reduced risk of pregnancy loss. In addition, luteal activity was significantly increased following GnRH treatment on Day 7 post-AI in drained cows.

Additional small dose of prostaglandin F2α at timed artificial insemination failed to improve pregnancy risk of lactating dairy cows.

Two experiments were performed to test the hypothesis that administering PGF2α concurrent with timed artificial insemination (AI) in lactating dairy cows would enhance pregnancy per AI (P/AI). In experiment 1, lactating Holstein cows (n = 289) in one herd were enrolled after a non-pregnancy diagnosis (30-36 d after AI) to synchronize subsequent ovulation before AI. Cows were assigned randomly to receive (im) 10 mg of PGF2α concurrent with timed AI (Day 0; treatment) or no injection (control). Blood samples were collected on Days -3, 0, and 13 to determine serum concentrations of progesterone. Ovaries were scanned via transrectal ultrasonography to determine follicle diameters (Day -3), subsequent ovulation risk (Day 13), and total volume of luteal tissue (Day 13). Diagnosis of pregnancy occurred on Days 32 and 80 after AI. Ovulation risk post-AI exceeded 90% and did not differ between treatments. In addition, PGF2α treatment only numerically increased progesterone (5.7 ±â€¯0.3 vs. 6.2 ±â€¯0.3 ng/mL) or luteal tissue volume (8.9 ±â€¯0.4 vs. 9.8 ±â€¯0.5 ng/mL) on Day 13 by 8.8% (P = .206) or 10.1% (P = .134) in control and treated cows, respectively. Pregnancy per AI at Days 32 (P = .50) and 80 (P = .33) did not differ between treatments. Cows with progesterone >0.5 ng/mL at timed AI had reduced (P < .001) ovulation risk but risk was unaffected by treatment. In experiment 2, lactating dairy cows (n = 1828) in two commercial dairy herds were enrolled at time of insemination (Day 0), and assigned randomly to treatment or control as described in experiment 1. Initial (Days 32-35) and confirmed (Days 63-68) pregnancy diagnosis revealed no differences in P/AI or pregnancy loss. Pregnancy diagnosis on Days 32-35 produced percentage increases in P/AI for primiparous compared with multiparous cows (20.8%; P = .002), for first-service compared with repeat-service cows (26%; P = .001), and cows in one herd compared with the second herd (36%; P < .001). Pregnancy loss was greater (P = .001) for cows inseminated at first (10.0%) vs. later services (5.3%) but was unaffected by treatment. Cows treated with PGF2α in one herd produced more twins than control cows (11.7 vs. 3.2%), whereas no treatment difference was detected in the second herd (5.6 vs. 5.6%), respectively. We conclude that im treatment of lactating dairy cows with 10 mg of PGF2α concurrent with timed AI did not improve P/AI or embryo survival, but increased twinning in one herd.

A prospective comparison of vasopressor requirement and hemodynamic changes during spinal anesthesia for cesarean delivery in patients with multiple gestation versus singleton pregnancy.

BACKGROUND: It is commonly taught that patients with multiple gestation pregnancy are prone to more severe hypotension during spinal and epidural anesthesia compared to those with singleton pregnancy. However, few quantitative data are available to support this claim. In this study, we prospectively compared vasopressor requirement and hemodynamic changes in patients with multiple gestation versus singleton pregnancy during spinal anesthesia for elective cesarean delivery. METHODS: Forty parturients with multiple gestation and 60 singleton controls who had identical anesthetic management during spinal anesthesia for elective cesarean delivery were enrolled. After IV prehydration, patients received intrathecal bupivacaine-fentanyl and were tilted to the left. A metaraminol infusion was titrated with the target of maintaining systolic blood pressure at 90%-100% of baseline. Vasopressor dose, minimum and maximum values for systolic blood pressure and the incidences of hypotension, hypertension, and nausea/vomiting were compared. RESULTS: All outcome variables were similar between groups. The total dose of metaraminol required until uterine incision was similar in multiple gestation pregnancy (median 2.9 [interquartile range 2.0-3.7] mg) when compared with singleton pregnancy (median 3.1 [interquartile range 2.3-3.9] mg, P = 0.25; median difference 0.30 mg, 95% confidence interval of difference -0.20 to 0.90 mg). Neonatal outcome was similar between groups. CONCLUSION: Patients with multiple gestation pregnancy do not exhibit greater hemodynamic instability during spinal anesthesia for cesarean delivery compared to those with singleton pregnancy.

Progesterone supplementation in the early luteal phase after artificial insemination improves conception rates in high-producing dairy cows.

This study examines the possible effects on the reproductive performance of high-producing dairy cows of progesterone (P4) given in the early luteal phase (1.55 g of P4), from Days 3 to 5 post-artificial insemination (AI) as compared with the time of pregnancy recognition, from Days 15 to 17 post-AI. Cows in their third day post-AI were alternately assigned on a weekly rotational basis to the following groups: control, no treatment (C: n = 351), P4 treatment started 15 days after AI (P4-D15: n = 261), or P4 treatment started 3 days after AI (P4-D3: n = 203). Based on odds ratios, cows in P4-D3 were 1.71 times more likely to conceive than control cows (P = 0.004), whereas cows in P4-D15 showed a 1.4-fold greater risk approaching significance of becoming pregnant compared with control cows (P = 0.06). Differences were not observed between treatments. In nonpregnant cows, the given treatment (D3 vs. D15) had no effect on subsequent return to estrus or AI interval and neither were any effects of treatment observed on early fetal loss rates. In contrast, in pregnant cows, the relative risk of twin pregnancy was 2.5 times higher for those in P4-D15 (P = 0.02) than the remaining cows. These findings indicate the efficacy of P4 supplementation after AI. However, when given at the time of pregnancy recognition rather than in the early luteal phase, this treatment increases the twin pregnancy rate.

Ovarian Stimulation, Intrauterine Insemination, Multiple Pregnancy and Major Congenital Malformations: A Systematic Review and Meta- Analysis- The ART_Rev Study.

INTRODUCTION: Multiple pregnancies are a recognized adverse effect of assisted reproductive technologies; nevertheless, there is no consensus on the incremental risk associated with the ovarian stimulation (OS) used alone and intrauterine insemination (IUI). The relationship between OS and IUI and the risk of major congenital malformations (MCM) is unclear. OBJECTIVE: To summarise the literature and evaluate the risk of multiple pregnancy and MCM associated with OS used alone and IUI used with or without OS compared to natural conception (spontaneously conceived infants without any type of fertility treatments). METHODS: We carried out a systematic review to identify published papers between 1966 and 2014 in MEDLINE, EMBASE and the Cochrane Central Register of Controlled Trials. We included observational studies and randomized clinical trials related to the risk of multiple pregnancies and MCM conceived following OS alone or IUI compared to natural conception (spontaneously conceived infants without any fertility treatments). The quality of the included studies was evaluated using The Cochrane Collaboration's tool for assessing risk of bias for RCTs and the Newcastle-Ottawa Scale for observational studies. RESULTS: There were 63 studies included in this review. Our systematic review suggests that the use of any OS alone was associated with an increased risk of multiple pregnancy compared to natural conception (pooled RR 8.80, 95% CI 5.09- 15.20; p= 0.000; 9 studies). Similar increases in the risk of multiple pregnancies were observed following clomiphene citrate used without assisted reproductive technologies. Compared to natural conception, the use of IUI with or without OS was associated with an increased risk of multiple pregnancy (pooled RR 9.73, 95% CI 7.52 -12.60; p= 0.000; 6 studies). Compared to natural conception, the use of any OS alone was associated with an increased risk of any MCM (RR pooled 1.18, 95%CI 1.03-1.36; 11 studies), major musculoskeletal malformations (pooled RR 1.48, 95%CI 1.21-1.81; 7 studies), and malformations of the nervous system (pooled RR 1.73, 95%CI 1.15-2.61; 6 studies). Compared to natural conception, the use of IUI was associated with an increased risk of any MCM (pooled RR 1.23, 95%CI 1.10-1.37; 10 studies), major urogenital (pooled RR 1.52, 95%CI 1.04-2.22; 7 studies), and musculoskeletal malformations (pooled RR 1.54, 95%CI 1.20-1.98; 7 studies). The overall quality of the included studies was acceptable. CONCLUSIONS: The increased risk of multiple pregnancy and certain types of MCM associated with the use of less invasive fertility treatments, such as OS and IUI, found in this review, highlights the importance of the practice framing. Heterogeneity in OS protocols, the combination with other fertility agents, the limited number of studies and the methodological quality differences reduce our ability to draw conclusions on specific treatment. More observational studies, assessing the risk of multiple pregnancy or MCM, as a primary outcome, using standardized methodologies, in larger and better clinically defined populations are needed.

Folic acid supplementation and the occurrence of congenital heart defects, orofacial clefts, multiple births, and miscarriage.

Key research findings relative to the question of whether maternal use of folic acid before and during pregnancy reduces the chance that offspring will be born with a congenital heart defect or an orofacial cleft are reviewed in this paper. Observational studies in general support an association between maternal use of multivitamins containing folic acid and a reduction in the occurrence of congenital heart defects and orofacial clefts. Results from one randomized controlled trial (RCT) provide the strongest evidence that multivitamins prevent congenital heart defects, but this RCT did not provide evidence that multivitamins prevent orofacial clefts. In addition, most observational and interventional studies are not designed to detect an independent effect from folic acid. Early studies suggested that periconceptional multivitamin use was associated with an increased occurrence of both miscarriages and multiple births, which has resulted in a great deal of controversy about the safety of folic acid use during pregnancy. We also review reports that were designed to answer these questions with more definitive data. When more substantial evidence about the effect of periconceptional folic acid on the occurrence of congenital heart defects and orofacial clefts is reported, we will have additional support for promoting folic acid intervention programs. All women capable of becoming pregnant should continue to consume 400 mug/d of folic acid in addition to a healthy diet as advised.

A protocol for the use of enoxaparin during pregnancy: results from 85 pregnancies including 13 multiple gestation pregnancies.

Many practitioners consider low-molecular-weight heparin (LMWH) an alternative to unfractionated heparin, although there are limited safety data regarding maternal and fetal outcomes in patients using an LMWH during pregnancy. A retrospective chart review was performed on 72 patients with thrombophilia exposed to the LMWH, enoxaparin, during pregnancy. Eighty-five pregnancies resulted in 93 of 99 potential live births. Eleven of 12 twin pregnancies and one triplet pregnancy were successful. One preterm live birth infant of 33 weeks' gestation did not survive. Three patients with thrombophilia spontaneously aborted. A patient receiving injectable fertility treatment had spontaneously aborted one twin at 5 weeks' gestation. One patient terminated the pregnancy after discovering the presence of Down's syndrome. The mean maximum dose required to achieve a therapeutic anti-Xa level of 0.2-0.4 IU/mL at 5 to 6 hours following administration, was 38.1 mg every 12 hours (median 35 mg, range 30-75 mg every 12 hours). The mean anti-Xa level was 0.28 IU/mL (median 0.3, range 0.05-0.8 IU/mL). A total of nine patients experienced bleeding events, two requiring discontinuation of enoxaparin for the remainder of the pregnancy. Two patients experienced injection site reactions requiring discontinuation of enoxaparin. Three patients developed preeclampsia, two placenta abruptio, and one placenta previa. No thromboembolic complications or osteoporotic fractures had occurred. Enoxaparin was safe and effective for preventing thromboembolism and adverse obstetrical complications in our patients, including 12 of 13 multiple gestation pregnancies.

Multivitamin supplementation and multiple births.

It is well established that maternal multivitamin supplementation reduces the risk of neural tube defects and evidence suggests that it may be associated with other reproductive outcomes. The present study was prompted by a report from a randomized trial in Hungary which showed a 40% increase in multiple births among periconceptional vitamin users. Retrospectively collected data on multivitamin supplementation were obtained on multiple and singleton births from three separate studies: Atlanta Birth Defects Case-Control Study (ABDCCS) malformed and nonmalformed infants born 1968-1980, California Birth Defects Monitoring Program (CBDMP) malformed and nonmalformed infants born 1987-1989, and Boston University Slone Epidemiology Unit Birth Defects Study (SEU-BDS) malformed infants born 1987-1994. Supplementation was divided into three mutually exclusive categories based on timing: "periconceptional" use--before through at least the third month after conception; "early" use--beginning in the first month and continuing through at least the third month after conception; and "later" use--beginning in the second or third month after conception. For periconceptional use, four of five datasets showed a 30 to 60% greater prevalence of supplementation among mothers of multiple births. In contrast, this pattern was not evident for "early" and "later" use. Overall, the study findings are tentative, due to a lack of consistency across all five datasets and they should not alter recent recommendations related to folate supplementation for the prevention of neural tube defects.

Successful twin pregnancy after renal transplant maintained on cyclosporine A immunosuppression.

Cyclosporine A has recently been reported to be an effective immunosuppressant agent for use in renal allograft recipients. Questions have been raised regarding its effects during pregnancy, in light of an increased life span and return of fertility in renal transplant patients. A preterm delivery is reported in a cadaveric renal allograft recipient chronically immunosuppressed with cyclosporine A and methylprednisolone. Dizygotic twins were delivered at 35 weeks' gestation, weighing 2452 and 2386 g. Maternal cyclosporine A levels were determined weekly by whole blood radioimmunoassay, with little increase in requirement found before delivery. No indication of maternal renal compromise was apparent, as evidenced by stable weekly creatinine clearance studies. Cyclosporine A, at the doses used, was passed transplacentally, with cord blood values of 34 and 57% of the maternal cyclosporine A level found at delivery. No adverse effects were noted at birth in the average for gestational age neonates, nor at nine-month follow-up evaluation. Given careful monitoring, cyclosporine A may be an effective immunosuppressant agent for use in pregnancies complicated by renal transplantation.

Elevated serum relaxin levels in multiple pregnancy after menotropin treatment.

The serum relaxin and human chorionic gonadotropin (hCG) concentrations were determined in 17 spontaneous singleton pregnancies and four singleton pregnancies and five multiple gestations that followed treatment with menotropins. The geometric mean serum relaxin concentrations for the control and postmenotropins singleton pregnancies were similar (both 1.13 ng/mL), but the geometric mean serum relaxin concentration for multiple gestations that followed treatment with menotropins was significantly higher (2.56 ng/mL, P less than .01). A significant regression of serum relaxin on either days from the last menstrual period or serum hCG concentration was demonstrated. Covariance analysis supported the conclusion that multiple gestation produced a significant increase in serum relaxin concentration.

Plasma estradiol window and urinary estriol glucuronide determinations for monitoring menotropin induction of ovulation.

The plasma estradiol response is maximal 8--10 hours following mentropin injection. To obtain closer control, a menotropin protocol using 5 PM--8 PM injections and 8 AM blood sampling with a plasma estradiol window of 1000--2000 pg/ml was evaluated with simultaneous calibration of a urinary estriol glucuronide radioimmunoassay. One hundred twenty-eight paired urine and plasma samples were assayed in 48 cycles. In 26 cycles with paired samples on the day of human chorionic gonadotropin (hCG) injection, there were no cases of severe hyperstimulation, 2 cases of moderate hyperstimulation, and 11 pregnancies (42% of cycles given hCG). A window of between 40 and 100 micrograms/day of urinary estriol glucuronide corresponded to the 1000--2000 pg/ml plasma estradiol window by regression analysis. The pregnancy and hyperstimulation rates were compared with those observed in protocols previously published. Radioimmunoassay of urinary estriol glucuronide is faster and simpler than radioimmunoassay of plasma estradiol.

Ovulation induction with subcutaneous pulsatile gonadotropin-releasing hormone: singleton pregnancies in patients with previous multiple pregnancies after gonadotropin therapy.

Three patients with hypothalamic amenorrhea who had previously had multiple pregnancies following gonadotropin therapy were treated with subcutaneous pulsatile gonadotropin-releasing hormone (GnRH), administered by a portable pump. After treatment with lower doses in some cases, pulses of 5 to 10 micrograms were given at 90-minute intervals, resulting in ovulation on six occasions. Ovarian steroid profiles closely resembled those of normal ovulatory cycles, and spontaneous ovulation of a single ovarian follicle was consistently demonstrated by ultrasound. Singleton pregnancy was confirmed in each patient. The results imply normal operation of the ovarian-pituitary feedback loop and suggest that subcutaneous pulsatile GnRH therapy is a safe and effective means of ovulation induction in clomiphene-resistant cases of hypothalamic amenorrhea and may possibly become the preferred method of treatment.

Ultrasonographic and clinical correlates of menotropin versus sequential clomiphene citrate: menotropin therapy for induction of ovulation.

Forty-six women remaining infertile with clomiphene citrate (CC) with or without human chorionic gonadotropin (hCG) were treated by either human menopausal gonadotropin (hMG, 44 cycles) or CC + hMG (33 cycles) and monitored by serum estradiol (E2) and ultrasonography. Ovarian hyperstimulation syndrome (OHS) and pregnancy outcome were compared in both regimens. In the presence of dominant follicles (greater than or equal to 18 mm) alone or with a single secondary follicle (14 to 16 mm) at hCG administration, OHS did not develop. A significant increase in OHS was noted when three or more secondary follicles were observed. Overall pregnancy rates were similar in both regimens but significantly higher when hCG was injected before rather than after the E2 peak. The results suggest secondary follicles rather than dominant follicles are a valuable sign of possible OHS development; and CC + hMG should be considered in CC-failure patients.