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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

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

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.

Adnexal Diseases

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

Pregnancy rate and ovarian hyperstimulation after luteal human chorionic gonadotropin in in vitro fertilization stimulated with gonadotropin-releasing hormone analog and menotropins.

The value of luteal phase supplementation with human chorionic gonadotropin (hCG) was assessed after a combined protocol of ovarian stimulation, using a long acting gonadotropin releasing hormone analog (GnRH-a) and human menopausal gonadotropins (hMG), in a randomized prospective study of 36 consecutive cycles in an in vitro fertilization (IVF) program. The patients were allocated on the transfer day to either luteal phase supplementation with hCG (Group A, n = 18) or none (Group B, n = 18). Nine patients of Group A conceived as compared with 3 in Group B. Five patients, all in Group A, developed ovarian hyperstimulation syndrome (OHSS) (3 moderate and 2 severe forms). Analysis of the hormonal profiles disclosed similar progesterone (P), estradiol (E2), and E2/P ratio up to the 6th post ovum pick-up day. Then, E2 and mainly P levels decreased only in Group B resulting in a rising E2/P ratio. These findings stress the importance of luteal support in IVF cycles treated with GnRH-a. In light of the increased risk of OHSS among hCG treated patients, further studies are needed to assess the optimal preparation needed.

Chorionic Gonadotropin

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

The effect of metoclopramide on ovarian responsiveness to gonadotropin administration in patients with severe polycystic ovarian syndrome.

Six patients with poor ovarian response to menotropin after pretreatment with a gonadotropin-releasing hormone analog exhibited improved ovarian responsiveness when metoclopramide was added on days 3, 5, and 7 of the cycle. This was evidenced by a higher number of leading follicles (4.4 versus 0.6), a higher mean of maximal serum 17 beta-estradiol levels (560 versus 178 pg/mL), a shorter duration of menotropin treatment (7 versus 11 days), and fewer ampules of menotropin used (20 versus 37 ampules/cycle) in metoclopramide-treated cycles as compared with control cycles, respectively. Serum prolactin levels reached a maximum of 172 ng/mL within 1 hour after metoclopramide administration and declined to normal range within 6 hours. These results suggest that intermittent increased prolactin secretion may augment ovarian response to gonadotropins.

Drug Therapy, Combination

The value of GnRH agonists in the treatment of failed cycles in an IVF-ET program: a comparative study.

Occasionally, menotropins fail to induce ovulation for IVF-ET, due to early luteinization resulting in high cancellation rates of 15-40% of cycles. The efficacy of GnRH agonists in reducing these problems was prospectively studied in 91 women undergoing repeated IVF-ET, after desensitization with GnRH agonists. In all patients, the cycles that had been induced by menotropins alone failed due to early luteinization. By comparing these patients to a control group with significantly lower cancellation rates as well as significantly higher fertilization, the cleavage and pregnancy rates were achieved for the former group (p less than 0.001 in all parameters). Pituitary down-regulation by means of GnRH agonists prior to the induction of ovulation seems to be an effective and rewarding method for minimizing cancellation rates, and for achieving improved results in IVF-ET therapy.

Adult