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PubMed1992

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↗

PubMed1990

Normoprolactinemic anovulation nonresponsive to clomiphene citrate: ovulation induction with bromocriptine.

Ovulation under bromocriptine was studied in 14 women with normoprolactinemic amenorrhea (5 primary, 9 secondary), unresponsive to clomiphene citrate (CC). On bromocriptine alone, ovulation occurred in 4 (28.6%). In the same subjects, bromocriptine was subsequently associated with CC. Seven patients ovulated (50.0%), including 3 that had responded to bromocriptine alone. Ovulation occurred once or twice in 6 of the 9 cases of secondary amenorrhea (66.6%). In several occasions, when ovulation induction failed, luteinized unruptured follicles were found under ultrasonographic monitoring. Four patients who had a negative response to progestin challenge did not ovulate with the treatment. Women with plasma prolactin in the upper normal range had a greater probability of achieving ovulation induction.

Adolescent↗

PubMed1990

Methods of ovulation induction.

The results of ovulation induction in patients with ovulatory dysfunction were reviewed for a one year period. Eighty-six women were assigned to four groups: secondary amenorrhea, anovulation, oligo-ovulation, and luteal phase defect/short luteal phase (LPD). All patients were monitored with basal body temperature (BBT) graph, postcoital testing, and ultrasonic scanning of ovarian follicles. All patients received therapy with clomiphene citrate (CC) for a minimum of four cycles and 13 patients conceived. Fifty patients were offered additional therapy with human menopausal gonadotropins (HMG-HCG). Seventeen completed a minimum of four cycles, and 13 conceived. The number of CC-treated patients with poor mucus quality in the face of adequate follicular development was 24, or 48%. The overwhelming problem with ovulation induction when CC failed was the large number of patients who dropped out of therapy, 48%. In summary, close monitoring during ovulation induction to confirm ovulation, and assess mucus quality and luteal function allow detection and correction of inadequate response. Induction of ovulation can be highly successful if patients can follow through and complete protocols of therapy.

Adult↗

PubMed1990

Alternate regimens for ovulation induction in polycystic ovarian disease.

The patient with PCOD remains a challenge to the reproductive endocrinologist. Although successful induction of ovulation can often be achieved using standard therapeutic regimens of CC or hMG, too often this group of anovulatory patients fails to respond as expected. Over the past 10 to 15 years, alternate approaches to ovulation induction have been investigated with encouraging results. Whereas no one method is productive in all patients, these varied regimens offer us a number of options in dealing with this difficult clinical problem.

Clomiphene↗

PubMed1992

[Ovulation induction with gonadotropins aided by cervix mucus analysis and echography].

Induction of ovulation was performed in 148 cycles using human menopausal gonadotropins (HMG) in 52 patients, seven with hypothalamic-pituitary failure and 45 suffering dysfunction at this level. Several induction schemes were used beginning on the second day of the cycle, until one or more follicles larger than 14 mm were found, to administrate 10,000 UI of human chorionic gonadotropin (HCG). Clinical valuation of cervical mucus and ultrasound of the ovaries to assess follicular development were done, from day eight of the cycle. Twenty five pregnancies resulted in 23 patients (44%), three in patients with failure and 22 in the dysfunction group. A total of 19 healthy babies were taken home, however three neonatal deaths, four miscarriages and one ectopic pregnancy occurred. Multiple gestation was present in three patients (12%), one was quadruplet, one triplet and one twin. The ovarian hyperstimulation syndrome (OHS) was detected in seven patients (13.4%), three were mild, two moderate and two severe; two cases of OHS had multiple pregnancies. Although induction of ovulation with HMG in patients with anovulation is a complex procedure requiring strict clinical vigilance and advanced technological resources, in this clinical study it was possible to obtain similar results to other series, using high resolution ultrasound only, without daily measurements of hormones.

Adult↗

PubMed1990

Accidental hyperstimulation during ovulation induction.

Clinical hyperstimulation is the most serious complication of ovulation induction, occurring in approximately 3% of cases (0.8% in the severe form). Paradoxically, it seems to be rare following in vitro fertilization, probably because all the follicles are aspirated. High-risk patients are those with polycystic ovarian disease, hyperprolactinaemia and hypothyroidism. All forms of ovulation induction have been implicated. Use of LHRH agonists have not reduced the incidence of hyperstimulation and they may even have increased it. An ongoing pregnancy seems to predispose to the occurrence of hyperstimulation, due to the secretion of hCG. Clinically, three stages of hyperstimulation have been described by the WHO (mild, moderate and severe). The pathophysiology is not completely understood, although prostaglandins, histamines and, especially, the ovarian renin-angiotensin system may be involved. Local ovarian complications and thromboembolic complications have also occurred. The treatment of severe hyperstimulation is both symptomatic (fluid replacement, aspiration of effusions, moderate sodium and water restriction, small doses of diuretics) and specific (corticosteroids, aspiration of ovarian cysts, even voluntary interruption of pregnancy in the most serious forms). If the hyperstimulation occurs in the absence of pregnancy, antihistamines or antiprostaglandins can be given. Prevention is exceedingly important. This can be helped by recognition of polycystic ovarian disease and stimulation of these cases by clomiphene citrate or pure FSH associated, for use in in vitro fertilization, with prolonged desensitization using LHRH agonists. Daily ultrasound and hormonal monitoring of ovulation induction is required. When there is excessive response to stimulation, it is prudent not to induce ovulation with hCG or, alternatively, to aspirate all the follicles and freeze the embryos obtained without giving further injections of hCG in the luteal phase. Clinical ovarian hyperstimulation is the classic form of iatrogenic disorder and is the most important complication of ovulation induction treatments, since it can be life-threatening in its most severe form. In this chapter we review current knowledge concerning the frequency, factors associated with its occurrence, clinical aspects, physiopathological mechanisms and, finally, the possibilities for treatment and prevention.

Female↗

PubMed1992

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↗

PubMed1992

[Ovulation induction by the chronic administration of naltrexone in a patient with secondary hypothalamic amenorrhea].

An ovulatory cycle was induced by oral administration of a specific opiate antagonist: naltrexone, at a dose of 50 mg/day for 26 days in a woman suffering from secondary hypothalamic amenorrhea. The follicular growth was monitored by ultrasound and serial blood measurement of LH, FSH, E2 and progesterone. The hormonal and ultrasound profiles showed an ovulatory cycle with a single dominant follicle. After discontinuation of the treatment, the patient became amenorrheic again. The gonadotropin as well as estradiol plasma levels declined, to that observed before treatment. Naltrexone may be a useful agent for induction of ovulation in women suffering from hypothalamic amenorrhea.

Adolescent↗

PubMed1992

Flow cytometric analysis of deoxyribonucleic acid in human granulosa cells as a function of chronological age and ovulation induction regimen.

We examined whether the proliferative index of granulosa cells as determined by flow cytometry varied with a women's age or ovulation induction regimen that included leuprolide acetate (LA). This prospective cohort study included three groups of patients undergoing assisted reproductive technologies. Group I consisted of 9 women age less than or equal to 30 yr, who received LA plus human menopausal gonadotropin (hMG). Group II included 9 women age more than or equal to 40 yr, who received LA plus hMG. Group III consisted of 6 women age less than or equal to 30 yr who received hMG alone. A total of 79 preovulatory follicles containing greater than 10(4) granulosa cells were obtained from these 24 women and examined by flow cytometry. Group I was compared to group II to match for ovulation induction regimen and to examine proliferative index as a function of age. Group I was compared to group III to match for age and to examine proliferative index as a function of ovulation induction regimen. Outcome measures included proliferative index of granulosa cells as a function of age, ovulation induction regimen, ampules of hMG, estradiol on day of hCG, and serum FSH. Group I demonstrated a greater proliferative index than group II: 23.4% +/- 1.4 vs. 18.4% +/- 0.96 (P less than 0.01). Group I had a greater proliferative index than group III: 23.4% +/- 1.4 vs. 11.9 +/- 0.61 (P less than 0.001). Although both age and the presence of LA appeared to affect the PI, multiple linear regression demonstrated that only the addition of LA and not age, per se, had an independent effect upon granulosa cells undergoing proliferation (P less than 0.0005). We conclude that LA followed by hMG leads to an increase in the percentage of granulosa cells undergoing proliferation when compared to ovulation induction regimens that include hMG alone. Chronological age does not appear to have a significant independent influence upon the proliferative index.

Adult↗

PubMedDate not supplied

Biochemical studies following ovulation induction with clomiphene citrate and human menopausal gonadotropin in infertile Indian women.

Biochemical studies were done in 65 anovulatory women before and following induction of ovulation with ethinyl estradiol/clomiphene citrate/human chorionic gonadotropin and also clomiphene citrate/human menopausal gonadotropin/human chorionic gonadotropin to determine the metabolic adverse effects, if any, of such therapy. Significant increases occurred in lipids and lipoprotein levels, while minor changes were seen in liver function enzymes and fasting blood sugar. Sialic acid decreased significantly after therapy in both the regimens, and both induction therapies seem to be free of adverse metabolic effects of hormones. On comparison with normal ovulatory women, this study suggests that some of the biochemical parameters can serve as reliable indicators of ensuing ovulation.

Adult↗

PubMed1990

[Clinical effects of pulsatile LH-RH administration on ovulation induction for women with various type of amenorrhea].

Using pulsatile LH-RH administration, ovulation induction was performed in women with pituitary dwarfism (PD, n = 1), isolated gonadotropin deficiency (IGD, n = 5), secondary hypothalamic amenorrhea (gestagen negative (AM2, n = 10), positive (AM1, n = 5)), polycystic ovarian disease (PCO, n = 6) and anovulatory cycle (ANOV, n = 1). Five to 20 micrograms of LH-RH was administered subcutaneously with a pulse frequency of 90 min to 2 h, in 76 treatment cycles. The ovulation rate of IGD, AM2, AM1 and PCO was 54.5, 83.3, 12.5 and 50.0%, respectively, all being significantly different from each other. In some cases, ovulation induction was repeated for several cycles without any interruption, and chronic effects of this therapy on the subsequent cycle were examined. In IGD and AM2, subsequent cycles were well stimulated, while those of PCO became refractory. These results indicate that pulsatile LH-RH administration should be the first choice of ovulation induction in IGD and AM2, and less effective in AM1 and PD. When this treatment is applied for PCO, the luteal phase should be supported by alternative methods to avoid pituitary desensitization.

Amenorrhea↗

PubMedDate not supplied

Ovulation induction increases serum levels of insulin-like growth factor binding protein 1.

The effect of ovulation induction on serum insulin-like growth factor binding protein 1 (IGFBP-1) level in relation to sex hormone binding globulin (SHBG) levels was evaluated. Serum samples were collected 8 to 12 days after ovulation from 26 women undergoing ovulation induction with clomiphene citrate (CC), and from 58 women treated with CC in combination with human menopausal gonadotropin (hMG) and human chorionic gonadotropin (hCG). In addition, serum samples were obtained from 63 spontaneously ovulating women and from 12 women during an anovulatory cycle. Luteal phase serum IGFBP-1 levels were 4.22 +/- 2.95 micrograms/L (P less than .05) in the CC group and 7.31 +/- 6.13 micrograms/L (P less than .001) in the CC/hMG/hCG group as compared to unstimulated ovulatory cycles (2.64 +/- 2.52 micrograms/L). No significant difference in IGFBP-1 levels was seen between spontaneously ovulatory and anovulatory cycles. The serum IGFBP-1 levels correlated positively to SHBG levels (r = .52, P less than .001). The data show that ovulation induction increases serum IGFBP-1 levels in parallel to SHBG levels, indicating that ovarian stimulation, which results in increased steroid hormone production, also induces changes in other factors known to modulate steroid hormone actions.

Anovulation↗

PubMed1992

Ovulation induction in women age 40 and older: the importance of basal follicle-stimulating hormone level and chronological age.

OBJECTIVES: To determine pregnancy and livebirth rates for women age 40 and older undergoing ovulation induction and to assess the impact of basal follicle-stimulating hormone (FSH) on outcome in these patients. DESIGN: Prospective, observational. SETTING: Fertility service of university medical center. PATIENTS: Infertile couples in whom the female partner was age 40 or older referred for ovulation induction therapy. INTERVENTION: Assessment of basal hormonal status; ovulation induction. MAIN OUTCOME MEASURES: Clinical pregnancy rate (PR), livebirth rate. RESULTS: Analysis of 402 cycles in 85 women age 40 and older demonstrated a clinical PR of 3.5% per cycle (95% confidence interval [CI] 1.7% to 5.3%). The livebirth rate was 1.2% per cycle (95% CI 0.1% to 2.3%). Women with a basal FSH < 25 IU/L and age < 44 years had a clinical PR of 5.2% per cycle (95% CI 2.5% to 7.9%) compared with 0.0% per cycle (95% CI 0.0% to 2.1%) in cases in which either basal FSH was > or = 25 IU/L or age was > or = 44 (P < 0.005). The prognostic importance of basal FSH and chronological age was confirmed by multivariate logistic regression analysis. The predictive value of the resulting regression equation was high (R2 = 0.94; P < 0.01). CONCLUSIONS: Pregnancy and livebirth rates are generally low during ovulation induction in women age 40 and older. In combination, basal FSH and chronological age are accurate predictors of PR, in these couples and can define a subset of patients with a more favorable prognosis. The spontaneous abortion rate in women who do conceive is high, substantially lowering the livebirth rate.

Adult↗

PubMed1992

The appearance of one-pronuclear human oocytes is associated with a better ovulation-induction response and successful pregnancy outcome.

OBJECTIVE: To study the relationship between the presence of one-pronuclear oocytes in in vitro fertilization (IVF) patients and ovulation-induction response, oocyte and embryo development, and clinical outcome. DESIGN: Retrospective analysis of 535 consecutive IVF retrievals. Retrievals in which one or more oocytes exhibited one pronucleus were compared with retrievals in which no one-pronuclear oocytes (control) were observed. The following one-pronuclear versus control subgroups were also examined: leuprolide acetate/human menopausal gonadotropin (LA/hMG) ovulation inductions, high estradiol (E2) response cases, and retrievals in which a large number of oocytes (greater than or equal to 15) were recovered. SETTING: Brigham and Women's Hospital, a tertiary care, university-affiliated hospital. PATIENTS: Three hundred forty-six IVF patients were treated between January 1989 and May 1991. MAIN OUTCOME MEASURES: Parameters examined included E2 concentration and number of follicles with maximum diameter greater than or equal to 12 mm on day of human chorionic gonadotropin administration; number of total and mature oocytes retrieved; total fertilization rates; number of embryos; and percent per retrieval of embryo transfers (ETs), clinical pregnancies, and ongoing-livebirths. RESULTS: The one-pronuclear patients had higher E2 levels and larger number of follicles, yielded significantly more total and mature oocytes, had a higher overall fertilization rate, produced more embryos, and had higher ET, clinical pregnancy and ongoing-livebirth rates per retrieval than did the control patients. Analysis of the subgroup populations revealed no significant differences in the majority of the main outcome measures studied; however, the one-pronuclear patients yielded significantly more total and mature oocytes per retrieval. CONCLUSIONS: Although there was an increase in the clinical and ongoing-livebirth pregnancy rates (PRs) in one-pronuclear patients, this was probably associated with an improved ovulation-induction response in the one-pronuclear patients. They achieved significantly higher E2 levels, recruited a larger number of follicles, and yielded more oocytes and embryos per retrieval than the control patients. When only the LA/hMG, E2 greater than or equal to 1,500 pg/mL, or the greater than or equal to 15 oocytes/case retrievals were analyzed, the PRs were no longer different; however, the one-pronuclear patients still yielded significantly more total and mature oocytes per retrieval than the controls. Therefore, the appearance of one-pronuclear oocytes is probably associated with the maturation stage of the oocytes obtained and is indicative of an ovulation induction in which a large number of preovulatory, metaphase II oocytes have been recruited.

Cell Nucleus↗

PubMed1992

Growth hormone (GH)-binding protein regulation by estrogen, progesterone, and gonadotropins in human: the effect of ovulation induction with menopausal gonadotropins, GH, and gestation.

The recently described serum GH-binding protein (GH-BP) may reflect the GH-receptor level. To assess the serum GH-BP levels under various physiological and supraphysiological levels of sex steroids, we have evaluated its concentration in 26 patients undergoing 34 cycles of ovulation induction with either human menopausal gonadotropins (hMG)/hCG or GH/hMG/hCG. The latter ovulation induction protocol was undertaken in "Clonidine negative" patients in a prospective, randomized, crossed-over manner, between GH/hMG/hCG or hMG/hCG. The increase in GH-BP levels in patients' sera undergoing ovulation induction directly correlated with peripheral estradiol (E2) (r = 0.577; P < 0.001), and with peripheral progesterone (P4) (r = 0.542; P < 0.001; n = 174) concentrations in hMG/hCG cycles, and also in GH/hMG/hCG cycles (r = 0.669, P < 0.001 for E2, and r = 0.722, P < 0.001 for P4, n = 84). GH-BP levels did not change significantly in response to 0.15 mg Clonidine ingestion. The baseline GH-BP levels significantly correlated with the body mass index of 47 patients (r = 0.547; P < 0.001). The insulin-like growth factor-I (IGF-I) concentrations increased in correlation with increasing E2 levels up to 5500 pmol/L but decreased thereafter, at very high E2 concentrations. In gestations generated by ovulation induction with hMG/hCG or GH/hMG/hCG, longitudinal measurements of GH-BP levels showed an initial sharp increase during early gestation, followed by a gradual decrease beginning around the end of the first trimester and continuing during the mid and late trimesters. In normal spontaneous pregnancies, GH-BP levels, measured from the fifth week until term, were negatively correlated with gestational age (r = -0.581; P < 0.001; n = 84). This pattern is highly suggestive of the possibility that GH-BP is coregulated not only with E2 and P4 but also with hCG, and possibly other gonadotropins as well. Indeed, in patients with "resistant ovaries", pharmacological amounts of hMG failed to increase E2 concentrations but moderately increased GH-BP levels. These data provide good indirect evidence for coregulation of the GH-BP with both sex steroids and gonadotropins. The mid and late trimesters decrease in GH-BP levels in spite of increasing sex steroids concentrations, may be attributed to the decreasing hCG concentrations, and/or to the increasing secretion of placental lactogen (PL) and placental GH with the advancing gestation.

Carrier Proteins↗

PubMed1992

Effects of smoking on ovulation induction for assisted reproductive techniques.

OBJECTIVE: To determine the effects of smoking on ovulation induction for assisted reproductive techniques. DESIGN: Matched, retrospective, cohort study. SETTING: Outpatient University endocrine/infertility program. PATIENTS: Eighteen smokers and 36 nonsmokers: 2 nonsmokers matched to each smoker for age, weight, and history of ovarian surgery. MAIN OUTCOME MEASURES: During a stimulation cycle, the serum estradiol (E2) level, number of follicles, number of oocytes, number of embryos, and ampules of gonadotropins used were compared in the smoking versus the nonsmoking groups by Wilcoxon's signed rank test for paired data. Follicular fluid (FF), testosterone (T), androstenedione (A), E2, A:E2 ratios, and T:E2 ratios were measured and compared between groups by Mann-Whitney U-tests. RESULTS: Smokers had significantly lower serum E2 levels, fewer follicles, fewer oocytes retrieved, and fewer embryos per cycle than nonsmokers, despite equal amounts of gonadotropin administration. Follicular fluid obtained from mature follicles had a higher A:E2 ratio and a higher T:E2 ratio in smokers compared with nonsmokers. CONCLUSIONS: Smoking adversely affects ovulation induction parameters and alters the FF hormonal milieu.

Adult↗

PubMed1992

Ovulation induction with a single-blind treatment regimen comparing naltrexone, placebo and clomiphene citrate in women with secondary amenorrhea.

Secondary amenorrhea is often associated with emotional stress, weight loss, eating disorders or polycystic ovary-like disease. Involvement of the endogenous opioids in the pathophysiology of hypothalamic amenorrhea, by inhibition of hypothalamic GnRH secretion, has been demonstrated in some cases. Chronic blockade of the endogenous opioids with the long-acting opioid antagonist naltrexone could result in increased gonadotropin secretion and ovulation induction in these cases. A single-blind ovulation induction protocol comparing naltrexone, placebo and clomiphene citrate was evaluated in eight patients with secondary amenorrhea. Naltrexone proved not to be more effective than placebo in our study. Only one patient ovulated on naltrexone, one on placebo and four on clomiphene citrate. The latter therapy caused a better endocrine response. In conclusion, although ovulation could be incidentally induced by naltrexone, this drug did not appear to be more successful than placebo and clomiphene citrate for ovulation induction in this population of patients.

Amenorrhea↗

PubMed1991

Is it possible to run a successful ovulation induction program based solely on ultrasound monitoring? The importance of endometrial measurements.

OBJECTIVE: To attempt the monitoring of ovulation induction solely with ultrasound (US). DESIGN: Using serial US measurements to monitor ovulation induction using human menopausal gonadotropin and human chorionic gonadotropin (hCG), in comparison with estradiol (E2) concentrations that became available at the end of each cycle. SETTING: Specialist Reproductive Endocrine Unit. PATIENTS, PARTICIPANTS: Twenty hypogonadotropic and 29 ultrasonically diagnosed polycystic ovary patients. MAIN OUTCOME MEASURE: Follicular growth, uterine measurements, endometrial thickness, and serum E2 concentrations. RESULTS: Follicular growth, uterine measurements, and endometrial thickness correlated strongly with E2 concentrations (P less than 0.0001). The endometrium on the day of hCG administration was significantly thicker (P less than 0.01) in the conception (n = 27) compared with the nonconception cycles (n = 87), whereas no significant difference were observed in serum E2 concentrations. No pregnancy was observed when hCG had been administered when the endometrial thickness was less than or equal to 7 mm. Midluteal endometrial thickness of greater than or equal to 11 mm was found to be a good prognostic factor for detecting early pregnancy (P less than 0.008). CONCLUSIONS: Serial US examinations used alone have proven to be safe and highly efficient. It also has a unique ability to detect pregnancy in the midluteal phase.

Adult↗