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Prospective randomized study of human menotropin versus a follicular and a luteal phase gonadotropin-releasing hormone analog-human menotropin stimulation protocols for in vitro fertilization.

OBJECTIVE: To determine whether gonadotropin-releasing hormone analogs (GnRH-a) initiated either in the luteal phase or in the early follicular phase immediately preceding menotropin will improve the fertilization, implantation, and pregnancy rates (PR) in all IVF patients, when compared with menotropins alone. DESIGN: In a prospective, controlled, randomized study we compared a pure follicle-stimulating hormone (FSH) human menopausal gonadotropin (hMG) protocol (group A = control) (n = 93 cycles) to two protocols in which GnRH-a pretreatment plus pure FSH and/or hMG was used in in vitro fertilization candidates. In group B (n = 64) GnRH-a was initiated during the luteal phase and in group C (n = 35) during the follicular phase. RESULTS: We found (1) no differences in fertilization and implantation rates between the three protocols; (2) similar pregnancy rates per transfer when similar number of conceptus were transferred (A = 30%, B = 22%, C = 21%); (3) an increase of the number of oocytes obtained; and (4) a reduction in the cancellation rate with both GnRH-a protocols. CONCLUSIONS: These findings suggest that there is no obvious superiority between the two GnRH-a protocols in the dosage schedule used and that the major advantage of GnRH-a over non-GnRH-a protocols is in decreasing the cancellation rate and increasing the number of oocytes and conceptus obtained. The follicular phase GnRH-a protocol required less hMG-pure FSH than the luteal phase GnRH-a protocol.

Adult↗

Menotropins alone are superior to a clomiphene citrate and menotropin combination for superovulation induction among clomiphene citrate failures.

OBJECTIVE: To examine the difference in efficacy between two protocols of superovulation induction with IUI among infertile couples. DESIGN: A prospective randomized trial. SETTING: Normal human volunteers in an infertility clinic. PATIENTS: Consecutively treated patients attending our infertility clinic for superovulation induction with IUI who had been unsuccessfully treated by clomiphene citrate (CC). INTERVENTIONS: Infertile couples were randomized to undergo one of two controlled ovarian hyperstimulation protocols. Group A patients received daily hMG beginning on cycle day 3, whereas group B patients were administered CC days 3 through 7, followed by hMG from day 7 onward. Randomization was performed using a random numbers table. In both groups, ovulation was triggered by 5,000 IU hCG and IUI was performed by 36 hours. MAIN OUTCOME MEASURES: Studied cycle performance parameters included peak E2, number of dominant and intermediate-sized follicles recruited, endometrial thickness and pattern, and frequency of monitoring. RESULTS: Data analysis demonstrated no significant difference between the two groups with respect to patient age, parity, weight, indication for superovulation and IUI, number of dominant follicles recruited, peak E2, or mean number of total motile sperm inseminated. Endometrial thickness and pattern differed between treatments, however, with group A demonstrating relatively thicker and proportionately more trilaminar patterns than group B. Group A had significantly more serum E2 measurements, as well as transvaginal sonograms performed, when compared with group B. Pregnancy rates for groups A and B were 0.192 and 0.091, respectively. Of 25 pregnancies in group A, 7 (0.28) were multiples, whereas there were no multiple gestations in group B. CONCLUSION: For patients undergoing superovulation with IUI, a menotropin-alone protocol yields significantly higher pregnancy rates than one using a combination of menotropin with CC. These differences could not be explained by patient characteristics. Among cycle performance parameters, endometrial thickness and pattern differed significantly between the two groups.

Adult↗

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.

Chorionic Gonadotropin↗

Lutropin alfa: new preparation. Combined with follitropin for follicular development: no better than menotropin.

(1) The reference ovarian stimulant for women with severe FSH and LH deficiency and pituitary dysfunction is menotropin (postmenopausal urinary human gonadotrophin (hMG)). (2) A recombinant LH, lutropin alfa, has now been licensed for this use, in combination with recombinant FSH (follitropin alfa or follitropin beta). The evaluation file contains no data from trials comparing the follitropin-lutropin alfa combination with menotropin. (3) Two dose-finding studies involving a total of 78 women, and a double-blind trial comparing follitropin + placebo with follitropin + lutropin alfa, have shown that 75 IU/day lutropin alfa yields satisfactory follicular development in two-thirds of women whose plasma LH concentration is below 1.2 IU/I. Efficacy has not been demonstrated in women with higher plasma concentrations of LH. Similar results have been reported with menotropin. (4) The adverse effect profile of the follitropin + lutropin alfa combination is similar to that of menotropin. The main risk is an ovarian hyperstimulation syndrome. Monitoring of plasma estradiol concentrations, pelvic ultrasound findings, and clinical state are required to avoid severe ovarian hyperstimulation. There is no evidence that the risk differs between menotropin and the follitropin + lutropin alfa combination at adjusted doses. (5) In France, the combination of follitropin alfa + lutropin alfa costs about five times more than menotropin. (6) Menotropin remains the first line ovarian stimulant for women with severe deficiency of FSH and LH.

Double-Blind Method↗

Alteration of ascending thoracic aorta compliance after treatment with menotropin.

OBJECTIVE: Our purpose was to determine whether aortic size and compliance are altered by an exogenously induced rise in estrogen. STUDY DESIGN: Magnetic resonance imaging was used to determine the aortic cross-sectional area/aortic pressure relationship in nine premenopausal women before and after menotropin therapy. Simultaneous electrocardiograms, carotid pulse tracings, phonocardiograms, and brachial artery pressures were obtained before each magnetic resonance imaging acquisition. Ascending thoracic aorta cross-sectional area was obtained every 32 msec and aligned with brachial artery pressures extrapolated from the carotid pulse tracing, allowing construction of the ascending thoracic aorta cross-sectional area/aortic pressure relationships. Aortic cross-sectional area was normalized to body surface area, and the shifts in the position for the ascending thoracic aorta cross-sectional area/aortic pressure relationship were determined with use of analysis of covariance. RESULTS: Heart rate and aortic pressure were unchanged before and after menotropin treatment. Initial estradiol levels were < 20 pg/ml. After menotropin treatment (7.4 +/- 1.0 days) estradiol levels rose to 905 +/- 371 pg/ml (p < 0.0001). Ascending thoracic aorta cross-sectional area/body surface area was not significantly increased, adjusted y mean of 389 +/- 7 mm2/m2 before and 403 +/- 7 mm2/m2 after menotropin treatment (p < 0.24). The slope of the ascending aorta cross-sectional area/aortic pressure relationship, an index of aortic compliance, increased from 1.4 +/- 0.6 mm2/m2/mm Hg before to 1.7 +/- 0.6 mm2/m2/mm Hg after menotropin treatment (p < 0.001). CONCLUSION: In premenopausal women a short-term rise in estrogen induced by menotropin treatment is associated with an increase in aortic compliance. Aorta size is not significantly increased within this time frame.

Adult↗

Ultrasound evaluation of estrogen monitoring for induction of ovulation with menotropins.

Twenty-five cycles of induced ovulation with menotropins were investigated blindly with ultrasound to evaluate estrogen monitoring. Plasma 17 beta-estradiol (E2) and urinary estriol glucuronide (E3G) correlated with total ovarian volume (0.58, 0.58), total follicular volume (0.56, 0.52), volume of the largest follicle (0.53, 0.54), and days of administration of menotropins (0.49, 0.44), respectively. The mutual correlations of days of menotropin administration, volume of the largest follicle, E2, and E3G with total follicular volume explained the correlations of E2 and E3G with days of administration of menotropins and with volume of the largest follicle. Thus, multiple small follicles can reproduce the E2 or E3G levels associated with a single mature follicle if they result in the same total follicular volume. As menotropins were administered for progressively longer periods, the number of maturing follicles increased. We conclude that ultrasound appears to be useful for monitoring induction of ovulation with menotropins since it provides more accurate information on follicular number and size than can be obtained by estrogen determinations alone.

Chorionic Gonadotropin↗

Risk factors for spontaneous abortion in menotropin-treated women.

Women who conceive with human gonadotropins have a high rate of spontaneous abortions. The causes for this poor outcome are unknown. In a retrospective analysis, the authors analyzed potential factors in 45 menotropin-treated patients with spontaneous first-trimester miscarriages. Data were compared with 119 menotropin-treated patients who conceived and delivered viable infants. Patient factors that were analyzed included the following: age, history of past miscarriages, duration of infertility, diagnostic category, weight, body surface area, duration and weight-corrected dose of menotropin administration, maximum estradiol level, estradiol pattern, human chorionic gonadotropin (hCG) dose, presence or absence of hCG support in the luteal phase, results of postcoital testing, methods of insemination, and results of husband's semen analysis. There was a significant difference between the miscarriage group and the control group in regard to age and weight distribution. All other characteristics were not significantly different. Patients over 81.8 kg as well as patients aged 35 years and older were both significantly (P less than 0.01) at increased risk to have a spontaneous first-trimester miscarriage. The data suggest that obesity and advanced age contribute to the high miscarriage rate in menotropin-treated patients. It appears reasonable to suggest that women weighing more than 81.8 kg should make every effort to lose weight before beginning menotropin therapy.

Abortion, Spontaneous↗

[Early use of menotropin in the treatment of varicocele].

INTRODUCTION AND OBJECTIVES: Varicocele is the most common disease in infertile men and varicocelectomy remains the main treatment. During the last years a lot of drugs have been proposed in association with surgery. The aim of this study is verify the effects of the association between menotropin and subinguinal varicocelectomy on sperm parameters and pregnancy rate. METHODS: 60 patients with left varicocele were randomized in three groups of 20 patients: patients of group A were treated with menotropin since diagnosis for three months; patients of group B were treated with menotropin but started the treatment three months after surgical treatment; patients of group C were treated only with varicocelectomy. We have tested sperm parameters before and after three, six and twelve months from surgical treatment. After six and twelve months from varicocelectomy we have verified the pregnancy rates in the three groups. RESULTS: After three months from surgical treatment, sperm parameters were significantly improved only in the group A (p < 0.05). After six months we have recorded a similar improvement even in the group B. After twelve months we have confirmed a significant improvement in groups A and B; the values were significantly higher than in the group C (p < 0.05). After six months the pregnancy rate was 42%, 25% and 22.2% respectively in the three groups. After twelve months we have recorded an important improvement of pregnancy rate in groups A and B (47% and 45% respectively) and a little improvement (27.7%) in group C. CONCLUSIONS: Our data show a significant improvement of sperm parameters in the two groups treated with menotropin respect to the group treated with only varicocelectomy. It could be responsible for a similar improvement of the pregnancy rate. The association between varicocelectomy and early use of menotropin seem to improve testis functional rehabilitation.

Adult↗

[Ovarian hyperstimulation with menotropins as treatment for unexplained sterility; effect of reproductive characteristics on the results].

The objective was to evaluate the utility of the ovarian hyperstimulation with menotropins as treatment of unexplained infertility. One hundred couples with unexplained infertility were treated. Ovarian stimulation was started with 150 IU of menotropins on day 3 of the menstrual cycle, monitoring the follicular growth with transvaginal ultrasonography, additional doses of menotropins were administered accordingly. Human chorionic gonadotropin (10000 IU) was administered when the dominant follicle reached a diameter > or = 16 mm. The pregnancy rate per cycle was 12.0%, on the other hand the cumulate rate of pregnancy was 48.0%. The age under 30 years and the antecedent of previous pregnancies were correlated with the likelihood of conception. The spontaneous abortion rate was 35.4%. As conclusion, it therefore appears appropriate, to offer a treatment with menotropins to that specific group of couples with unexplained infertility with good prognostic factor as age < 30 years and infertility duration < 5 years. The increase on the spontaneous abortion rate was probably induced for the luteal insufficiency produced by the ovarian hyperstimulation with menotropins.

Abortion, Spontaneous↗

Luteinzing hormone activity in menotropins optimizes folliculogenesis and treatment in controlled ovarian stimulation.

Although the role that LH plays in folliculogenesis is still controversial, recent evidence points toward facilitatory actions of LH activity in ovulation induction. Thus, we compared the response to either highly purified FSH (75 IU FSH/ampoule; group A, 25 subjects) or human menopausal gonadotropin (75 IU FSH and 75 IU LH/ampoule; group B, 25 subjects) in normoovulatory GnRH agonist-suppressed women, candidates for intrauterine insemination. A fixed regimen of 2 daily ampoules of highly purified FSH or human menopausal gonadotropin was administered in the initial 14 days of treatment; menotropin dose adjustments were allowed thereafter. Treatment was monitored with daily blood samples for the measurement of LH, FSH, 17beta-estradiol (E(2)), progesterone, testosterone, hCG, inhibin A, and inhibin B, and transvaginal pelvic ultrasound was performed at 2-day intervals. Although preovulatory E(2) levels were similar, both the duration of treatment (16.1 +/- 0.8 vs. 12.6 +/- 0.5 days; P< 0.005) and the per cycle menotropin dose (33.6 +/- 2.4 vs. 23.6 +/- 1.1 ampoules; P < 0.005) were lower in group B. In the initial 14 treatment days the area under the curve of FSH, progesterone, testosterone, inhibin A, and inhibin B did not differ between the 2 groups, whereas LH, hCG, and E(2) areas under the curve were higher in group B. The occurrence of small follicles (<10 mm) and the inhibin B/A ratio in the late follicular phase were significantly reduced in group B. A nonsignificant trend toward a higher multiple gestation rate was present in group A (60% vs. 17%). We conclude that ovulation induction with LH activity-containing menotropins is associated with 1) shorter treatment duration, 2) lower menotropin consumption, and 3) reduced development of small ovarian follicles. These features can be exploited to develop regimens that optimize treatment outcome, lower costs, and reduce occurrence of complications such as multiple gestation and ovarian hyperstimulation.

Adult↗

Menotropins as a possible risk factor for premature deliveries in triplet pregnancies.

This study was undertaken in order to evaluate pregnancy outcome in three groups of triplet conceptions. Of 36 delivered triplet gestations, seven were spontaneous, 12 achieved using clomiphene citrate and 17 induced by menotropins. The mean gestational age (weeks) at delivery was 36.5 +/- 1.0 SD, for spontaneous and clomiphene citrate pregnancies it was 35.9 +/- 1.9 SD which differed significantly from that in pregnancies induced by menotropins which was 32.9 +/- 3.7 SD. Similarly, triplets born following menotropin treatment had a significantly lower gestational weight (g) of 1656 +/- 516 SD vs. 2015 +/- 198 SD and 2176 +/- 315 SD for spontaneous and clomiphene citrate gestations, respectively. It is concluded that triplets following menotropins are at an increased risk for premature delivery and low birth weight.

Adult↗

A life-table analysis of pregnancy yield in fixed low-dose menotropin therapy for patients in whom clomiphene citrate failed to induce ovulation.

Forty-nine patients in whom clomiphene citrate failed to induce ovulation were treated for 177 cycles with a fixed low dosage of menotropin. Among these 49 patients, there were 24 pregnancies. Among these pregnancies were two that were multiple and three spontaneous abortions. In only one treatment cycle was there a hyperstimulation syndrome. These patients were divided into three clinical groups: the secondary amenorrheic patient, the oligo-amenorrheic patient, and the patient with poor corpus luteum function. There was no statistically significant difference in the pregnancy rate per month among all groups during the first three treatment cycles (average value, 0.07). However, there was a statistically significant improvement in the pregnancy rate per month in the group with secondary amenorrhea and the group with poor corpus luteum in the last three treatment cycles, as compared with the first three treatment cycles (P = 0.05; average value, 0.75). The oligo-amenorrheic patients, on the other hand, during the last 3 months of treatment, had no statistically significant increase in the pregnancy rate per month. These data suggest that menotropin therapy may have a priming effect. These data do not fit the currently accepted model of a constant pregnancy rate per month for all patients. The data suggest that caution should be exercised before combining patient groups when evaluating the results of menotropin therapy.

Amenorrhea↗

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.

Abortion, Spontaneous↗

Eliminating the risk of life-endangering complications following overstimulation with menotropin fertility agents: a report on women undergoing in vitro fertilization and embryo transfer.

OBJECTIVE: To evaluate a new method for preventing the life-endangering complications associated with inadvertent menotropin-induced severe ovarian hyperstimulation in patients undergoing in vitro fertilization and embryo transfer (IVF-ET). METHODS: Seventeen women each underwent a single cycle of controlled ovarian hyperstimulation with menotropins in preparation for IVF-ET. The indications for IVF-ET were tubal occlusion in nine, endometriosis in six, and unexplained infertility in two. The peak plasma estradiol (E2) concentration before hCG administration was greater than 6000 pg/mL and more than 30 ovarian follicles were detected by transvaginal ultrasound. Thus, life-endangering complications associated with severe ovarian hyperstimulation syndrome were highly likely to occur following hCG administration. Rather than cancel the cycle of treatment, menotropin therapy was discontinued and hCG administration was deferred for a number of days until the plasma E2 concentration fell below 3000 pg/mL ("prolonged coasting"), whereupon hCG was administered and egg retrievals and ETs were duly performed. RESULTS: None of the women developed severe ovarian hyperstimulation syndrome. There were six viable pregnancies (35.2%), which proceeded normally. CONCLUSION: This study indicates that "prolonged coasting" prevents severe ovarian hyperstimulation syndrome in severely overstimulated women undergoing IVF-ET, without necessitating cycle cancellation.

Adult↗

Induction of ovulation with menotropins in women with polycystic ovary syndrome.

Twenty-four women with ovulatory infertility as a result of surgically or biochemically documented polycystic ovary syndrome (PCO) who had failed to conceive during clomiphene citrate therapy underwent a closely supervised menotropin treatment to induce ovulation. Evidence of ovulation was obtained in all patients treated, and major side effects were limited. Fourteen women conceived after an average of 2.4 treatment cycles; twin pregnancies occurred in 36% and spontaneous abortions occurred in 21%. Initial treatment cycles tended to be less successful than the subsequent treatment cycles. Serum 17 beta-estradiol (E2) levels were significantly augmented in the last 3 days before administration of chorionic gonadotropins (hCG) in treatment cycles resulting in conception compared to E2 levels in those cycles which resulted in ovulation only. A second hCG administration to trigger ovulation had to be given in 27% of the treatment cycles and seemed to be an indication of a less promising treatment cycle. Treatment cycles resulting in twin gestations did not differ from those resulting in singleton gestations; specifically, the E2 response was not increased. In summary, under a closely monitored regimen, menotropin therapy can be used in women with nonovulatory infertility as a result of PCO with considerable effectiveness and relative safety once clomiphene citrate treatment has failed.

Abortion, Spontaneous↗

Sequential clomiphene citrate-menotropin therapy for induction or enhancement of ovulation.

Either to induce ovulation in anovulatory infertility patients or to enhance ovulation in patients with mild endometriosis or luteal phase inadequacy, we utilized a sequential regimen of low-dose clomiphene citrate (CC) followed by human menopausal gonadotropin (hMG) injections on alternate days; duration and dosage of menotropin therapy was individualized by using serum estradiol levels for monitoring until the time of administration of human chorionic gonadotropins. Previous therapeutic efforts without menotropins had been unsuccessful in all patients. One third of 70 treated patients conceived during 156 treatment cycles. The pregnancy rate was 44% in anovulatory patients (n = 34), and 26% in patients with ovulation dysfunction (n = 23). Pregnancy rates declined with patient's age. Four of the 23 patients that conceived had a spontaneous abortion (17%). The multiple gestation rate was 10.5%. A relative inhibition of cervical mucus development was noted and shown to be caused by CC. Hyperstimulation occurred in three patients. The discussed CC-hMG regimen approaches the effectiveness of standard hMG therapy; but compared with standard hMG therapy, it has significant economic advantages and seems to have a markedly lower rate of multiple gestation. However, like standard hMG therapy, CC-hMG therapy requires careful monitoring specifically, because hyperstimulation may occur.

Adult↗

Plasma estradiol is superior to ultrasound and urinary estriol glucuronide as a predictor of ovarian hyperstimulation during induction of ovulation with menotropins.

In order to compare the effectiveness of 8:00 A.M. plasma 17 beta-estradiol (E2), 24-hour urinary estriol glucuronide (E3G), and ultrasound as predictors of ovarian hyperstimulation, 70 cycles of induction of ovulation with 5:00 P.M. to 8:00 P.M. injection of menotropins from 28 subjects were evaluated. Hyperstimulation was four times more frequent in pregnancy than in nonpregnancy cycles (P less than 0.005). The hyperstimulation score (range, 0 to 6) was correlated with plasma E2 (0.63, P less than 0.01), the number of follicles (0.31, P less than 0.05), the duration of treatment (0.31, P less than 0.05), and urinary E3G (0.25, P less than 0.05). Plasma E2 was the best predictor of the hyperstimulation score, and plasma E2 was far superior to both urinary E3G and the number of follicles. Management with ultrasound alone is insufficient to prevent severe ovarian hyperstimulation. With this protocol, human chorionic gonadotropin may be given as soon as the first follicle reaches 1.4 cm in diameter as long as plasma E2 is less than 4000 pg/ml. The values of plasma E2 are dependent on the interval between blood sampling and injection of menotropins.

Estradiol↗

The difference in miscarriage rates between menotropin-induced and natural cycle pregnancies is not surveillance related.

OBJECTIVE: To assess the reportedly higher miscarriage rate during menotropin-induced cycle pregnancies as compared with natural cycle. DESIGN: Prospective cohort groups were selected, and pregnancies were identified 16 to 18 days after insemination and followed through to outcome. PATIENTS: Three hundred twelve patients were studied: 251 women receiving human menopausal gonadotropin and 61 requiring donor insemination without medication. RESULTS: A significant difference between the spontaneous abortion rate of gonadotropin-treated women (28.5%) and women conceiving during natural cycles (11.7%) was demonstrated. CONCLUSION: The opinion that higher miscarriage rates in menotropin-treated women are related to a surveillance bias compared with natural cycle conceptions should be reconsidered.

Abortion, Spontaneous↗