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A new concept of cotreatment with human growth hormone and menotropins in ovulation induction protocols.

Follicular development in the primordial and preantral stages is almost completely independent of gonadotrophins or steroids and is mainly dependent on growth factors and local regulators. Since human growth hormone (hGH) was found to facilitate ovarian response to gonadotrophin stimulation, we hypothesized that the administration of hGH in an hypogonadotrophic state and prior to ovarian stimulation with menotropins, may initiate or facilitate the propagation of the primordial and preantral follicles to the gonadotrophin-dependent stages. We suggest that treatment with hGH prior to menotropin administration may be useful to improve results for poor responders to gonadotrophins.

Clinical Protocols↗

Plasma dehydroepiandrosterone sulfate serves as a prehormone for 48% of follicular fluid testosterone during treatment with menotropins.

Evidence has suggested that dehydroepiandrosterone sulfate (DS) is a prehormone for ovarian steroidogenesis. To study this hypothesis, combined 6-h infusions of [3H]dehydroepiandrosterone sulfate and [14C]testosterone ([14C]T) were performed in four normal women treated with menotropins who were undergoing medically indicated surgery, and the data were compared to those from nine normal women. The concentrations of tracer and nonisotopic DS, androst-5-ene-3 beta,17 beta-diol sulfate (delta 5diolS), androst-5-ene-3 beta,17 beta-diol (delta 5diol), dehydroepiandrosterone (D), androstenedione (delta 4A), and T were determined in arterial and venous blood and in follicular fluid. From these data, the concentrations and fractions of steroids in the follicular fluid that were derived from DS were calculated from the specific activity of intravascular DS and the concentrations of follicular fluid tracer steroids and their specific activities. The fractions of T (0.48), delta 5diol (0.31), delta 5diolS (0.42), and D (0.25) in follicular fluid arising from circulating DS were similar and were not significantly different from that of follicular DS arising from circulating DS (0.32). However, the fraction of follicular fluid delta 4A (0.041) was significantly less (P < 0.01), and the fractions of intrafollicular estrone and estradiol arising from DS were both less than 0.04. The mean MCR of DS in the women treated with menotropins of 22.0 +/- 3.5 L/day (mean +/- SE) was significantly higher than the normal control value. These findings elucidate an important mechanism of adrenal/ovarian interaction at the level of steroidogenesis; circulating DS serves as a prehormone for the production of intrafollicular delta 5diolS, delta 5 diol, D, and T.

Adult↗

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↗

[The use of clomiphene and menotropins as inducers of multiple follicular growth in a program of in vitro fertilization].

In our IVF & related techniques program, clomiphene 50 mg was used from days 2 to 6 of the cycle in 20 patients and 20 cycles. (17 IVF patients and 3 GIFT patients) menotropins were also used in 2 different schemes: a) 2 ampules in alternated days (12 cases) and b) one ampule daily (8 cases). The patients with the daily scheme required lesser total dose of menotropins and developed higher estradiol levels, although this had none statistic significance, and they also developed a greater number of follicles. There were 16 laparoscopies for ovum capture and 53 oocytes were retrieved (30.2% mature) 10 oocytes were from the GIFT patients. 16 oocytes were fertilized and 8 cleaved. There was only one pregnancy from and IVF patient with the alternated scheme that ended with a first trimester abortion.

Adult↗

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.

Chorionic Gonadotropin↗

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↗

Postcoital testing in women during menotropin therapy.

The authors were interested in determining the predictive value of postcoital testing in women who undergo human menopausal gonadotropin (hMG) therapy for the induction of ovulation. Fifty consecutive patients were studied whose husbands had acceptable semen analyses; 24 of the patients conceived. Postcoital testing was done after hMG stimulation on the day human chorionic gonadotropins (hCG) were given or the day before. All but one patient had excellent cervical mucus quality. Sperm characteristics in cervical mucus were analyzed in regard to overall motility, number of active sperm per high-power field (HPF), and quality of movement. These data were correlated with outcome in terms of conception. A linear correlation could be shown between overall motility and pregnancy outcome once at least 40% motility was present; no pregnancy occurred in patients with 20% or less sperm motility. Once five or more active sperm/HPF were noted, the chance of pregnancy was about 60%; this chance was not increased with higher density rates. In all but one patient who conceived, sperm with maximum quality (+3 motility) were noted. Data were compiled in a postcoital score (range 0 to 12). Patients with a high score had a pregnancy rate of 70%, patients with an intermediate score, 23%, and none of the seven women with low scores conceived. Because menotropin therapy is costly, demanding, and potentially risky, it is suggested that one utilize results of postcoital testing as a guide in decisions about the continuation of such therapy.

Cervix Mucus↗

Diagnosis-specific serum 17 beta-estradiol (E2) upper limits for treatment with menotropins using a 125I direct E2 assay.

Statistical evaluation of 133 cycles of induction of ovulation using generalized linear models demonstrated that the occurrence and severity of ovarian hyperstimulation was influenced by the serum 17 beta-estradiol (E2) concentration (P less than 0.001), conception (P less than 0.001), and the endocrinologic diagnosis, polycystic ovary syndrome (PCO) or hypothalamic amenorrhea (HA) (P less than 0.01). When menotropins were administered between 5:00 P.M. and 8:00 P.M. and blood was drawn at 8:00 A.M., an upper limit for serum E2 in patients with HA of 2417 pg/ml or an upper limit for patients with PCO of 3778 pg/ml gave an approximate 5% risk of severe ovarian hyperstimulation in conception cycles and a 1.3% risk of severe hyperstimulation in nonconception cycles. Comparison of our E2 radioimmunoassay involving extraction and chromatography to the Pantex immunodirect Estradiol 125I kit (Pantex, Santa Monica, CA) demonstrated no detectable systematic error, allowing the use of these limits with either assay. The ovulating injection of human chorionic gonadotropin was given at 5:00 P.M. to 8:00 P.M. on the evening of blood drawing as soon as the first follicle reached an average diameter of 14 mm or greater. The ultrasound parameters allow the chance of pregnancy to be optimized and the chance of multiple gestation to be minimized. Serum E2 monitoring indicates when the risk of ovarian hyperstimulation is too great for human chorionic gonadotropin to be given.

Amenorrhea↗

Timing and frequency of artificial insemination in women under menotropin therapy.

The timing and frequency of AID were reviewed in 36 women who received menotropin therapy. One hundred thirteen treatment cycles were reviewed with AID done once per cycle in 39, twice per cycle in 63, and three times per cycle in 11 cases. The pregnancy rate was 19.5% per treatment cycle, with 21 of the 36 patients (58%) conceiving. No difference in pregnancy rate was found with single or multiple inseminations when AID application included the day of hCG administration. Evidence is presented that suggests that frequently the fertilizing sperm may have resided in the woman for over 30 hours before fertilization occurred.

Chorionic Gonadotropin↗

Pregnancy induced with menotropins in a woman with polycystic ovaries, endometrial hyperplasia, and adenocarcinoma.

A 31-year-old woman is described with PCOD associated with endometrial hyperplasia and well-differentiated adenocarcinoma. Conservative treatment with ovulation induction was pursued for a total of 3 1/2 years. After CC treatment failed to achieve conception, treatment with menotropins resulted in a twin pregnancy that aborted spontaneously and a singleton term pregnancy. Hysterectomy was performed 4 1/2 years after the initial diagnosis of well-differentiated endometrial adenocarcinoma was made. Histologic examination of the endometrium showed no progression of the disease. Ovulation induction of patients with polycystic ovaries and well-differentiated and noninvasive endometrial adenocarcinoma may be justified in properly selected cases.

Adenocarcinoma↗

Periovulatory 17 beta-estradiol pattern in conceptional and nonconceptional cycles during menotropin treatment of anovulatory infertility.

The value of multiple parameters in the prediction of fertile cycles was prospectively evaluated in 52 menotropin-induced cycles. The periovulatory pattern of estradiol (E2) was found to correlate with conceptional cycles. E2 levels greater than 500 pg/ml on the day of human chorionic gonadotropin administration (day 0) with a further increase on day +1 (high ascending pattern--A1) were found to have a 51% predictive value for fertile cycles. Twelve of the 17 fertile cycles had an A1, type of response (71%), whereas the overall incidence of an A1 pattern was 42% (22 of 52). No pregnancies have occurred with preovulatory follicles less than or equal to 14 mm in diameter. The number of preovulatory follicles, E2 level on day 0, and midluteal progesterone had no predictive value for fertile cycles.

Anovulation↗

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↗

Ovarian hyperstimulation syndrome following D-Trp-6 luteinizing hormone-releasing hormone microcapsules and menotropin for in vitro fertilization.

In 143 cycles of in vitro fertilization the ovarian hyperstimulation syndrome (OHSS) occurred in 12 (8.4%) cycles. Six were in the moderate form and 6 severe. Ovarian stimulation by menotropins was preceded by induction of hypopituitary hypogonadism using D-Trp6-LH-RH microcapsules. The OHSS cycles are characterized by improved ovarian response expressed by the increased serum levels of estradiol, number of follicles, oocytes, embryos and pregnancy rate as compared to cycles with no OHSS. All patients recovered uneventfully. The follicular puncture did not have the suggested protective effect against OHSS. It is suggested that the substantial incidence of OHSS is probably related to the excessive ovarian stimulation not interrupted by early luteinization which is practically abolished by this protocol. The role of the given luteal hCG doses in the genesis of OHSS is questioned.

Adult↗

Lack of association between ovarian follicular size and number and the occurrence of multiple pregnancies in menotropin cycles.

A high rate of ovarian multifollicular development and resulting multiple pregnancy remains the main problem of ovulation induction with human menopausal gonadotropins. The aim of this study was to examine a possible correlation between the number and size of ovarian follicles at the time of human chorionic gonadotropin (hCG) administration and to find parameters that can predict the occurrence of multiple pregnancies. Sixty-eight intrauterine pregnancies, 53 singletons and 15 multiple pregnancies in 51 patients, were included in this study. We found no significant difference in the mean estradiol levels, the total number of pre-ovulatory follicles, or the mean number of large, intermediate or small follicles at the time of hCG administration between women who had singleton pregnancies and those with multiple pregnancies. Our study demonstrates that estradiol levels and ovarian ultrasonography do not provide criteria for the prediction of the occurrence of multiple pregnancies in menotropin cycles.

Chorionic Gonadotropin↗

The impact of GnRH agonist and menotropin therapy on lipoprotein metabolism.

Two groups of women, 48 undergoing controlled ovarian hyperstimulation for in vitro fertilization (IVF) treatment with a gonadotropin-releasing hormone (GnRH) analog and human menopausal gonadotropin daily and a group of 15 treated with a GnRH analog using the 'luteal phase protocol' before the hyperstimulation for IVF, took part in a prospective randomized study at the IVF Unit of the Beilinson Medical Center, Israel. The aim was to evaluate the changes in lipid metabolism occurring in the course of a standard controlled ovarian hyperstimulation protocol during IVF treatment cycles by measuring serum lipid levels before and after treatment. In the former group, in parallel with the 17 beta-estradiol increase, the cholesterol and low-density lipoprotein-cholesterol levels dropped and the high-density lipoprotein-cholesterol levels increased significantly. The resultant atherogenic index demonstrated a statistically significant decrease. In the latter group the mean lipoprotein levels were slightly different after treatment, but no statistically significant difference was observed. Our results indicate that the GnRH analog alone, administered for 10-12 days, does not induce any significant change in serum lipid levels. When using a combination of a GnRH analog and menotropins, the change of lipoprotein levels is favorable.

Adult↗

Effect of body mass index and follicular synchrony in the ovarian response to ovulation induction with menotropins.

OBJECTIVE: To determine the correlation between body mass index, follicular synchrony, and pregnancy rate in a controlled ovarian hyperstimulation program with menotropins. SUBJECTS AND METHODS: Seventy-nine hyperstimulation cycles were evaluated. Transvaginal ultrasonographic control was performed and 10,000 IU of human chorionic gonadotropin were administered when the dominant follicle reached a diameter > 16 mm. In order to evaluate the follicular response, the ovarian synchrony factor was used (# follicles > or =16 mm/# follicles > 10 mm). For the statistical analysis, linear correlation and chi-square tests were used. RESULTS: When patients had a normal body mass index there was a positive correlation ( r = .52) between body mass index (kg/m(1.5)) and the ovarian synchrony factor. Weight deficiency and obesity had a deleterious effect on the ovarian response ( r = -.47 and r = -.77, respectively). There was a significant difference in the number of pregnancies in patients with ideal weight in relationship to the subgroup with weight deficit. CONCLUSIONS: An adequate body constitution increases the possibilities of achieving success in ovulation induction programs; on the other hand, weight disturbances have a deleterious effect on ovulation.

Body Mass Index↗