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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 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

Menotropin stimulation after prolonged gonadotropin releasing hormone agonist pretreatment for in vitro fertilization in patients with endometriosis.

Two protocols were scheduled for in vitro fertilization and embryo transfer (IVF-ET) in patients with various stages of endometriosis who were resistant to conventional therapies. In the ultralong protocol (21 patients), gonadotropin releasing hormone agonist (Gn-RHa) was administered for at least 60 days prior to ovarian stimulation along with menotropin until human chorionic gonadotropin was injected. In the long protocol (11 patients), Gn-RHa was started at the midluteal phase and exogenous gonadotropin was commenced between the third and the seventh day of the menstrual cycle after pituitary suppression. The estradiol response and the number of retrieved oocytes, fertilized oocytes, cleaved oocytes, and transferred embryos were similar in both groups but the clinical pregnancy rate per transfer was superior in the ultralong protocol (67 vs 27%). The miscarriage rate was 14% (2/14) in the ultralong protocol. Prolonged Gn-RHa suppression of ovarian function before superovulation may overcome some causes of infertility in patients with endometriosis.

Adult

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.

Female

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.

Abortion, Spontaneous

Use of granulosa-luteal cell culture to evaluate low and high clinical responses to menotropin stimulation.

The cause of a poor response to human menopausal gonadotropin (hMG) remains unexplained. To determine whether aromatase activity of cultured granulosa cells obtained from relatively low estradiol (E2) responders (serum E2 < 1000 pg/ml) to hMG therapy differed from that of good responders (E2 > or = 1000 pg/ml), we prospectively compared serum E2 on the day of human chorionic gonadotropin administration to in vitro aromatase activity following a 72-h culture. Granulosa cells were obtained from seven women undergoing hMG therapy and oocyte aspiration. Follicle stimulating hormone (FSH) was added to one-half of the cultures. Serum E2 was determined by radioimmunoassay, and aromatase activity was determined indirectly by measuring tritiated water formed by aromatization of 1-beta [3H] androstenedione to estrogen in 1 h. In this study, luteinized granulosa cells from patients with a relatively low serum E2 produced less estrogen in cultures when compared to cells from higher responders (p < 0.01). Aromatase activity was not significantly increased by FSH in the relatively high responders, whereas FSH stimulated a significant increase in aromatase activity in cells from lower responders (p < 0.001). Our results indicate that the clinical response to hMG is at least partly due to the "quality" of granulosa cell aromatase activity. A clinically relevant "block" to FSH action may be present in vivo in low responders which can be reversed in culture by addition of FSH.

Aromatase

Early miscarriage and fetal malformations after induction of ovulation (by clomiphene citrate and/or human menotropins), in vitro fertilization, and gamete intrafallopian transfer.

From the reviewed data, it appears that CC, hMG-hCG, or the association of these drugs with IVF-ET and GIFT programs do not carry an increased risk for congenital malformations as a whole, nor is there any specific malformation that has an increased incidence or is related in any way with the use of these drugs. Table 7 represents the specific malformation rate per 1,000 births in the general population and in newborns delivered after treatment with CC, hMG-hCG, or IVF-ET and GIFT. The malformation rate in the treated groups does not differ from that of the general population. However, as shown by McIntosh et al., the incidence of congenital malformations often rises with a longer follow-up. Most of the reports about babies born after ovulation induction are based on the initial examination done shortly after birth. Thus, studies including examination of these infants up to at least 12 months of age will be undoubtedly of value. Also, data concerning the reproductive capability of women born after ovulation induction is lacking. With regard to the abortion rate in pregnancies achieved after such treatments and procedures, it can be concluded that it does not appear to be higher than that of the general population, particularly when early pregnancy loss, advanced maternal age, the infertility status, and the increased incidence of multiple pregnancies occurring in these patients are taken into consideration.

Abortion, Spontaneous

Ovarian hyporesponsiveness in combined gonadotropin-releasing hormone agonist and menotropin therapy is associated with low serum follicle-stimulating hormone levels.

The study was designed to evaluate if ovarian hyporesponsiveness, which is associated with combined gonadotropin-releasing hormone agonist (GnRH-a) and human menopausal gonadotropin (hMG) therapy is because of suboptimal serum follicle-stimulating hormone (FSH) levels. Two groups of 12 patients each were suppressed with GnRH-a and stimulation with a fixed dose of hMG. The control group (n = 10) received equal doses of hMG only. The follicular phase and the number of hMG ampules was significantly higher in the study group. Basal FSH levels and FSH levels during hMG treatment were significantly lower in patients treated with GnRH-a. Peak estradiol levels and the outcome of in vitro fertilization treatment were similar in the three groups. We suggest that the delay in ovarian response in patients treated with a combination of GnRH-a and hMG is because of lack of endogenous contribution of FSH, resulting in low circulating levels of FSH. An increase of serum FSH levels by administration of higher doses of hMG can reverse this effect.

Adult

Body weight, body mass index, and age: predictors of menotropin dose and cycle outcome in polycystic ovarian syndrome?

Whereas the dose of hMG is significantly correlated with both BMI and BW, commencing the more obese patient on higher hMG doses is not justified in view of the cancellation of cycles from over-responsiveness in the more obese patients started on higher hMG dosage regimens. If the more obese patient is slow to respond, however, a greater degree of clinical freedom may be exercised to increase the dose. The ultimate outcome of the cycle is not related to BMI, BW, or the dose of hMG used.

Aging

Ultrashort gonadotropin-releasing hormone agonist (GnRH-a) protocol in comparison with the long-acting GnRH-a protocol and menotropin alone.

OBJECTIVE: To compare the in vitro fertilization and embryo transfer (IVF-ET) outcome of a 3-day gonadotropin-releasing hormone agonist (GnRH-a) administration: ultrashort protocol with the outcome of long-acting GnRH-a cycles or human menopausal gonadotropin (hMG) alone. DESIGN: Ninety-two cycles of the ultrashort protocol were matched with 92 cycles with long GnRH-a and with 92 hMG cycles. SETTING: The IVF-ET program. MAIN OUTCOME MEASURES: Amount and duration of hMG treatment, hormonal profile on the day of human chorionic gonadotropin administration, cancellation rate, number of oocytes retrieved, and fertilization and pregnancy rates (PRs) were examined and compared among the three groups. RESULTS: The ultrashort group needed a higher number of hMG ampules than the hMG group but significantly less than in the long GnRH-a regimen. The number of oocytes in the ultrashort protocol was the same as in the long GnRH-a, but the number of embryos per retrieval was significantly lower than with the long GnRH-a protocol and similar to that found in the hMG group. The ultrashort protocol yielded 10% PR per cycle and 17% per replacement, significantly lower than with the long GnRH-a protocol, 26% and 36%, respectively, but also lower than in the hMG one, namely 13% and 28%. CONCLUSION: The ultrashort protocol, although being convenient and having some advantages found in the long GnRH-a protocol, is inferior in its outcome compared with the two other protocols.

Chorionic Gonadotropin

Ovulation stimulation and induction.

Evaluation of gonadotropins, prolactin, and thyroid function in anovulatory women directs subsequent therapy. Treatment should be initiated with the agent that is the safest and least costly for the specific indication. Except in cases of FSH elevation, pregnancy rates should approximate those of normally ovulating women. Bromocriptine, the drug of choice for hyperprolactinemia, restores ovulation in greater than 90% of women treated. Clomiphene citrate remains the drug of choice for normoestrogenic anovulation. Although drug-resistant women may respond to extended regimens, failure to ovulate or to conceive within six ovulatory cycles with clomiphene is an indication for menotropin therapy. Menotropins and pulsatile GnRH should be considered first line therapy for women with hypogonadotropic anovulation. When using hMG or pulsatile GnRH in clomiphene-resistant patients, pretreatment with GnRH analogs may normalize their response and result in higher pregnancy rates. GnRH analogs prevent premature luteinization in hMG-induced in vitro fertilization and gamete intrafallopian transfer cycles, resulting in lower cancellation rates and improved oocyte quality. Superovulation with clomiphene citrate should be attempted in patients with unexplained infertility prior to using menotropin therapy.

Bromocriptine

GnRH agonist increases pregnancy potential of retrieved oocytes given adequate preincubation before insemination: a comparative study.

Preincubation of oocytes aspirated from follicles in IVF-ET programs is a controversial approach. While some investigators recommend this technique others doubt its necessity. We have studied the embryo quality in 100 women, undergoing IVF-ET, in whom ovulation was induced by the combination of GnRH agonists (GnRHa) and menotropins and compared to a control group in whom ovulation was induced with menotropins alone. No statistically significant difference was noted with regard to the fertilization and cleavage rates as well as to the preincubation period. Significantly higher pregnancy rates (P less than 0.001) were encountered in the first group in comparison with the control group.

Female

Failed oocyte retrieval after lack of human chorionic gonadotropin administration in assisted reproductive technology.

OBJECTIVE: To document the absence of oocytes in follicular aspirates in women who, during controlled ovarian stimulation with gonadotropin-releasing hormone agonist (GnRH-a) and menotropins, fail to receive human chorionic gonadotropin (hCG) administration. DESIGN: Retrospective analysis of clinical laboratory data. SETTING: Multicentric. PATIENTS: Five women undergoing controlled ovarian hyperstimulation with GnRH-a and menotropins for programs of assisted reproductive technologies. RESULTS: The documented absence of an hCG injection produced "empty follicles" at transvaginal guided aspiration, despite numerous follicular lavages and aspiration of peritoneal fluid. The lack of oocytes and granulosa-cumulus complex in the follicular fluid was reverted in other cycles in the same patients when hCG was properly administered. CONCLUSIONS: (1) This study emphasizes the importance of proper patients' and nurses' instructions for preparation of hCG injections and proper mixture of vehicle and powder before follicular aspiration. (2) In the absence of cumulus-corona-oocyte complex at aspiration, measure serum beta-hCG to ascertain whether hCG injection was administered or not. (3) Routine preoperative beta-hCG levels may be helpful to avoid unnecessary surgeries.

Adult

Elevtion of serum testosterone in ovarian hyperstimulation syndrome.

Serum testosterone levels were monitored in female subjects who received therapy with human gonadotropins of urinary origin (menotropins) and human chorionic gonadotropin (hCG). Serum testosterone levels were not elevated in those subjects who did not experience side effects with therapy (Group A); among the other 7 subjects (Group B) with either moderate or severe ovarian hyperstimulation, serum testoterone levels rose distinctly (range 1.4 minus 9.0 ng/ml). Total menotropin dosage and serum estradiol-17beta levels were higher in Group B than in Group A. Ovarian hyperstimulation and elevation of serum testosterone were not restricted to patients with the syndrome of polycystic ovaries.

Chorionic Gonadotropin

The effect of ethinyl estradiol on endometrial thickness and uterine volume during ovulation induction by clomiphene citrate.

OBJECTIVE: To assess the deleterious effect of clomiphene citrate (CC) on the development of the endometrium and its improvement by the addition of ethinyl estradiol (E2). PARTICIPATING PATIENTS: Infertility-treated patients, monitored for induction of ovulation or timing of insemination (control group). DESIGN: We studied four groups of women during an ovulatory cycle with various treatment schedules. Group 1: untreated patients; group 2: patients treated by CC; group 3: patients treated by CC + ethinyl E2; group 4: patients treated by human menopausal gonadotropin. Follow-up of the patients was done by vaginal ultrasonography and measurements of blood E2. RESULTS: In the group treated by CC, both endometrial thickness and uterine volume growth during the follicular phase were lower as compared with untreated controls and menotropin-treated patients. The addition of ethinyl E2 to these patients reversed this deleterious effect of CC without interfering with ovulation. CONCLUSION: Ethinyl E2 may reverse the deleterious effect of CC on endometrial development during the follicular phase.

Adult

Ovulation induction protocols.

Ovulation induction protocols for oocyte retrieval have evolved from clomiphene citrate/human menopausal gonadotropins (menotropins) to human menopausal gonadotropins alone and, finally, to a combination of human menopausal gonadotropins and an agonist of gonadotropin-releasing hormone (GnRH-a). The almost abandonment of clomiphene use is due to findings from studies that showed reduced implantation due to the antiestrogen effect of clomiphene. The use of GnRH-a was introduced to maintain low levels of luteinizing hormone late in follicular development to prevent premature ovulation or premature senescence of the oocyte. The GnRH-a increases oocyte yield in poor responders, decreases cycle cancellations, improves the rate of pregnancy, and allows some control over the timing of retrieval. Attempts to use the GnRH-a to stimulate follicle maturation in a "short protocol" have resulted in variable and sometimes poor results. Therefore, the long GnRH-a/human menopausal gonadotropin protocol is currently used for most patients to prepare for oocyte retrieval.

Clinical Protocols