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.     

Variations of luteinizing hormone serum concentrations after exogenous human chorionic gonadotropin administration during ovarian hyperstimulation

Changes in luteinizing hormone (LH), estradiol, and progesterone (P) serum levels before and after preovulatory administration of human chorionic gonadotropin (hCG) were assayed in 30 patients stimulated with clomiphene citrate (CC) and human menopausal gonadotropin (hMG) and compared with LH variations in 43 patients submitted to pharmacological hypophysectomy with a gonadotropin-releasing hormone agonist (GnRH-a) and stimulation with hMG. In CC + hMG-treated patients, an endogenous LH surge occurred systematically 4.25 +/- 2.75 hours after hCG injection. Multiparametric analysis indicated an inverse correlation between the delay in the initial rise of the LH surge and the increase in P levels during the 6 hours after hCG administration. Gonadotropin-releasing hormone agonist + hMG treatment did not lead to an LH surge after hCG but to a significant fall in LH levels. Thus, exogenous hCG, administered before ovulation, induces an endogenous LH surge if pituitary function is not blocked by a GnRH-a, probably through an increase in P secretion.     

A comparison of leukocyte alkaline phosphatase and plasma estradiol measurements in the monitoring of clomiphene and gonadotropin therapy

Leukocyte alkaline phosphatase (LAP) and plasma estradiol (E2) were measured in 56 infertile women treated with clomiphene citrate and human chorionic gonadotropin (hCG) and in 21 infertile women treated with human menopausal gonadotropin (hMG) and hCG. Plasma LAP scores were found to correlate significantly with plasma E2 levels in both clomiphene- and hMG-stimulated patients, reflecting the depdence of LAP on the level of circulating plasma estrogens. However, the plasma LAP score failed to distinguish the difference between normal stimulated and hyperstimulated cycles following hMG administration. We conclude that plasma LAP measurements have little value in monitoring ovulation induction therapy.     

Successful induction of ovulation and conception with pulsatile intravenous administration of human menopausal gonadotropins in anovulatory infertile women resistant to clomiphene and pulsatile gonadotropin-releasing hormone therapy

Gonadotropins are released in a pulsatile fashion at a frequency of between 1 and 2 hours in the follicular phase of the menstrual cycle. Human menopausal gonadotropins are usually administered intramuscularly. We evaluated the gonadal response to intravenous human menopausal gonadotropins administered in a pulsatile fashion over nine treatment cycles in three anovulatory infertile women. Human menopausal gonadotropin pulses in doses up to 12 IU follicle-stimulating hormone at frequencies between 2 to 3 hours over 3 to 17 days resulted in ovulation in five cycles with one pregnancy being conceived. In the ovulatory cycles (5,000 to 10,000 IU of human chorionic gonadotropin was used to induce ovulation), the 17 beta-plasma estradiol level was 961 +/- 128 versus 326 +/- 95 pg/ml (mean +/- SEM) in the anovulatory cycles (p = 0.015). The dose of human menopausal gonadotropins (in ampules of Pergonal, 75 IU of follicle-stimulating hormone and 75 IU of luteinizing hormone) in the intravenous cycles needed to induce ovulation was 12.3 +/- 1.4 versus 20.4 +/- 0.9 for intramuscular cycles (n = 80 in 23 women, p = 0.008). Treatment was well tolerated and without complications. We are continuing to explore the use of this apparently more efficient mode of administering human menopausal gonadotropins to anovulatory patients resistant to other techniques of ovulation induction therapy.     

Improved pregnancy rate with monitoring of gonadotropin therapy by three modalities

The frequency of complications during gonadotropin therapy was reduced after the introduction of rapid estrogen assays. However, pregnancy rates remained low especially in normoestrogenic women. One hundred forty-three infertile normoestrogenic women were treated with human menopausal gonadotropin-human chorionic gonadotropin for 661 cycles. Almost all cycles were ovulatory. Whereas 53.7% of the patients conceived when drug administration was monitored by cervical score and serum estradiol levels only, 72.1% became pregnant when treatment was monitored by these modalities and real-time ultrasonography of the ovaries (p less than 0.05). Mean serum estradiol levels were significantly higher when ultrasonography was used to monitor response, but complications such as multiple births and ovarian enlargement did not occur more often. The data suggest that "true" ovulation occurs more often when ovarian imaging is used to determine drug dosage. Because of the higher pregnancy rate achieved by combined clinical (cervical score), biochemical (serum estradiol), and sonographic methods of monitoring, this approach should replace less extensive techniques.     

Delaying human chorionic gonadotropin administration in human menopausal gonadotropin-induced cycles decreases successful in vitro fertilization of human oocytes

Correct timing of human chorionic gonadotropin (hCG) administration in induced cycles for in vitro fertilization is of crucial importance to oocyte maturation and normal luteal function. The purpose of this work was to compare the effect of hCG timing on follicular development, oocyte maturation, and fertilization in vitro, as well as on the pattern of luteal phase hormone secretion. Ovulation was induced in 32 normally cycling women by human menopausal gonadotropin (hMG)/hCG administration. In the first group (17 women) 10,000 IU hCG was administered 24 hours after the last injection of hMG and in the second group (15 women) 48 to 72 hours after the last hMG injection. Serum estradiol levels prior to oocyte aspiration were similar in both groups, as were the numbers of large follicles on the day of hCG administration (4.5 +/- 2.3 versus 4.1 +/- 1.9 follicles/woman, respectively). The distribution of oocyte-corona-cumulus complexes was similar in both groups and was comprised of 11% immature, 43% intermediate, and 45% mature complexes. The fertilization rate, however, was significantly (P less than 0.001) reduced in the group treated by delayed hCG injection (57% versus 84%), and the percentage of degenerated oocytes was increased (9% versus 1%). Luteal phase length as well as progesterone and estradiol levels were comparable in both groups. It is concluded that an interval longer than 24 hours between the last injection of hMG and the administration of an ovulatory dose of hCG does not affect follicular and luteal phase serum steroid patterns but may result in a decreased oocyte fertilization rate, possibly due to atretic changes in the follicles.     

Sequential use of clomiphene citrate, human menopausal gonadotropin, and human chorionic gonadotropin in human in vitro fertilization. II. Study of luteal phase adequacy following aspiration of the preovulatory follicles

The 88 patients included in the in vitro fertilization program during 113 cycles were submitted to superovulation by sequential use of clomiphene citrate, human menopausal gonadotropin, and human chorionic gonadotropin. No correlation was found between estradiol and progesterone levels during the luteal phase and estradiol on the days preceding administration of human chorionic gonadotropin. Nineteen biopsies of the endometrium were carried out. The importance of the increase of estradiol between the day before and the day of administration of human chorionic gonadotropin is positively correlated with the quality of the endometrium.     

Luteal dysfunction in ovulation induction: the role of repetitive human chorionic gonadotropin supplementation during the luteal phase

Several studies have indicated that ovulation induction with human menopausal gonadotropin (hMG)/human chorionic gonadotropin (hCG) or clomiphene citrate (CC) is associated with luteal phase defect. To assess the efficiency of luteal support by hCG to an infertile population undergoing ovulation induction, with CC/hCG or hMG/hCG, we have randomly administered 2500 IU hCG intramuscularly on days 3, 6, and 9 after ovulation induction by 10,000 IU of hCG to 74 patients on 265 treatment cycles. As controls served 357 ovulation induction cycles in the same 74 patients. The treatment cycles were randomly alternated with control cycles so that each patient served as her own control. However, the mean +/- standard deviation (SD) midluteal P was 38.1 +/- 10.8 ng/ml in the study group versus 15.7 +/- 10.5 ng/ml in the control group (P less than 0.001). Luteal phase length was 15.4 +/- 1.5 days in the treatment group versus 12.1 +/- 1.7 in the control group (P less than 0.01). In the treatment group, 64.8% of the patients achieved pregnancy (27% pregnancies/treatment cycle) versus 47.3% in the control group (11.5% pregnancies/control cycle) (P less than 0.01). The pregnancy wastage rates (including abortions and "chemical" pregnancies) were 30.6% in the treatment group versus 56% in the control group (P less than 0.01). We conclude that repetitive hCG administration may be an efficient luteal support in infertile patients undergoing ovulation induction.     

Different hormonal patterns in human menopausal gonadotropin-treated, clomiphene citrate-treated, and untreated conception cycles

Serum concentrations of seven different hormones were analyzed during 189 singleton conception cycles. One hundred nine women were treated with human menopausal gonadotropin (hMG), 52 women received clomiphene citrate (CC), and 28 became pregnant spontaneously. Serum progesterone (P) levels in hMG-treated women started to increase on day 18 of the cycle and reached peak concentrations between days 28 and 32 of the cycle. Serum estradiol (E2) concentrations paralleled the P patterns. In hMG-treated women, there were significant correlations between serum E2 and P concentrations and the number of the mature follicles observed before ovulation (both P less than 0.01). CC-treated and spontaneous conception cycles revealed significantly lower serum levels of P, E2, testosterone, 17 alpha-hydroxyprogesterone, and prolactin, compared with hMG-treated cycles (P less than 0.05). Elevations of the gonadal steroids in hMG-treated women possibly reflect the multiple corpora lutea formed after multiple ovulations.     

Influence of corpus luteum age on the steroidogenic response to exogenous human chorionic gonadotropin in normal cycling women.

OBJECTIVE: The null hypothesis of this study is that the patterns of steroid secretion exhibited by the human corpus luteum in response to exogenous human chorionic gonadotropin stimulation are independent of corpus luteum age at the time of treatment. STUDY DESIGN: Twenty-five normally cycling women in whom the midcycle urinary luteinizing hormone surge (luteal day 0) was identified and from whom blood samples were obtained daily from cycle day 11 until menses were prospectively randomized to receive no treatment (group I, n = 5) or exogenous human chorionic gonadotropin 5000 IU administered intramuscularly on luteal day 0 (group II, n = 5), +4 (group III, n = 5), +8 (group IV, n = 5), or +12 (group V, n = 5). Serum concentrations of estrone, estradiol, progesterone, 17-hydroxyprogesterone, and androstenedione were measured by specific radioimmunoassays in all subjects; serum human chorionic gonadotropin concentrations were determined by immunoradiometric assay in treated subjects. RESULTS: Serum human chorionic gonadotropin levels (mean +/- SEM) were virtually identical among treatment groups (p greater than 0.05). Luteal phase duration (mean +/- SEM) was prolonged (p less than 0.05) only in group V (18.4 +/- 0.5 days) compared with untreated subjects (group I 13.8 +/- 0.7 days). In all groups estrone and 17-hydroxyprogesterone concentrations closely paralleled those of estradiol and progesterone, respectively. Steroid data and progesterone/estradiol ratios (mean +/- SEM) in groups I and II were indistinguishable and were combined (control, n = 10). Group III subjects exhibited patterns of steroid secretion similar to groups I and II, although progesterone was moderately increased after human chorionic gonadotropin treatment. In groups IV and V, progesterone increased (p less than 0.05) 1 day after human chorionic gonadotropin and remained elevated for 5 to 6 days; a 4-day rise (p less than 0.05) in estradiol began 3 days after treatment, and androstenedione rose modestly in parallel. Progesterone/estradiol ratios in groups III through V increased (p less than 0.05) approximately twofold after human chorionic gonadotropin treatment and remained elevated for 4 to 5 days. CONCLUSION: The human corpus luteum exhibits distinct age-dependent patterns of steroid secretion in response to exogenous human chorionic gonadotropin stimulation, an observation that may have clinical implications regarding the empirical use of exogenous human chorionic gonadotropin in support of luteal function.     

The use of high-dose human menopausal gonadotropin in an in vitro fertilization program

Sixty-three normal ovulatory women suffering from obstructive tubal disease not corrected by previous surgery were enrolled in an in vitro fertilization (IVF) program. To achieve a large number of mature follicles, a relatively high dose of human menopausal gonadotropin (hMG) was administered (19 +/- 4 ampules/cycle). Monitoring consisted of daily follicular ultrasonography and serum estradiol measurements. Human chorionic gonadotropin (10,000 IU) was administered when more than two large follicles (1.6 to 1.8 cm in diameter) were visualized. Fifty-five laparoscopies for oocyte retrieval were performed. A mean of 4.3 follicles per woman were aspirated, and 3.2 oocytes per woman were recovered. The oocytes were preincubated for 8 or 24 hours according to the morphologic degree of mucification and dispersal of the oocyte-corona-cumulus complex. Seventy-seven percent of the oocytes were fertilized and were transferred into the uterus 38 to 40 hours after insemination. Fifty-two women received one to eight embryos (mean, 3.5 +/- 1.9), and 9 (17%) conceived. This regimen of high-dose hMG precludes the need for serum or urine luteinizing hormone monitoring, because the occurrence of spontaneous ovulation is low. It is valuable in increasing the number of fertilizable oocytes, the percentage of women undergoing embryo transfer, and compensates with multiple oocyte transfer for the high embryonic loss involved in IVF.     

An extended regimen of clomiphene citrate in women unresponsive to standard therapy

An extended regimen of clomiphene consisting of 250 mg of clomiphene for 8 days followed by the administration of 10,000 IU of human chorionic gonadotropin (hCG) 6 days later was administered to 13 oligomenorrheic women who had previously failed to ovulate when treated with 250 mg of clomiphene for 5 days and hCG. Eight of these 13 women ovulated. Their postovulatory mean progesterone (P) level 7 days after hCG was 16 +/- 2 ng/ml. Three pregnancies occurred during 25 treatment cycles. Posttreatment estrogen levels were higher when women were treated for 8 days than for 5 days. Women ovulating after 8 days of treatment had increased concentrations of luteinizing hormone (LH) and testosterone (T) prior to hCG administration and higher pretreatment levels of estrogen and T, compared with women who did not ovulate. Changes in the timing of hCG administration may induce ovulation in some women who fail to ovulate when hCG is given on day 14. Because this 8-day regimen of clomiphene and hCG was successful in more than 50% of women failing to ovulate after 5 days, this regimen should be used prior to human menopausal gonadotropin (hMG) therapy.     

Insulin resistance and abnormal ovarian responses to human chorionic gonadotropin in chronically anovulatory women

We studied the interrelationships between insulin resistance, obesity, and abnormal ovarian androgen secretion in chronically anovulatory women with clinical or biochemical evidence of hyperandrogenism. Four groups of six subjects each were studied: (1) normal weight (within 10% ideal body weight) anovulatory, (2) obese (greater than 120% ideal body weight) anovulatory, (3) normal weight eumenorrheic, and (4) obese eumenorrheic. After dexamethasone suppression, human chorionic gonadotropin (2000 IU/1.5m2 body surface area intramuscularly) was administered to each subject. Serum testosterone levels were subsequently determined hourly for 17 hours. On a separate occasion, an oral glucose tolerance test was administered to five subjects from each group. Serum glucose and immunoreactive insulin levels were determined before and after the ingestion of a standard 100 gm glucose load. As a group, the anovulatory women had higher (p less than 0.05) basal testosterone levels (1005 +/- 97 pg/ml) than did the ovulatory women (241 +/- 21 pg/ml) (values +/- SE). Obesity per se was not associated with increased basal testosterone levels. Testosterone levels rose in response to human chorionic gonadotropin (p less than 0.005) only in obese anovulatory women, reached maximal levels after 3 hours, and subsequently remained stable. Basal immunoreactive insulin levels were elevated (p less than 0.05) only in obese anovulatory women (52.4 +/- 20 microU/ml) compared with obese eumenorrheic (8.7 +/- 1.0 microU/ml), normal weight anovulatory (5.8 +/- 2.4 microU/ml), and normal weight eumenorrheic (4.6 +/- 0.4 microU/ml) women. Similarly, maximal increases in immunoreactive insulin levels after glucose ingestion were significantly greater (p less than 0.01) in obese anovulatory women compared with other groups. Of note is the observation that maximal changes in testosterone observed within the first 3 hours after human chorionic gonadotropin and maximal changes in insulin were correlated (r = 0.91, p less than 0.01). These data suggest that (1) both insulin resistance and an abnormal acute response to human chorionic gonadotropin are seen only in obese anovulatory women and (2) the degree to which these two abnormalities are manifested is clearly correlated. The mechanism(s) responsible for this interrelationship, as well as the underlying cause(s) of these biochemical defects, remain to be elucidated.     

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.     

A prospective study of intrauterine insemination of processed sperm from men with oligoasthenospermia in superovulated women

The effectiveness of intrauterine insemination (IUI) was compared with that of intracervical insemination (ICI) in 49 infertile couples, in whom the major cause for infertility was oligoasthenospermia. All women had ovulation stimulated with either a clomiphene citrate (CC)-human gonadotropin combination or human gonadotropins alone. The ovulatory dose of human chorionic gonadotropin (hCG) was given after adequate estradiol levels were reached. The timing of inseminations was standardized--IUI was 28 hours after hCG and ICI was immediately after hCG administration. Only one insemination per month was performed with either IUI or ICI. The first treatment cycle was assigned randomly to be either IUI or ICI, and subsequent inseminations were alternated. A total of 182 cycles were completed, with 96 IUIs and 86 ICIs. Pregnancy occurred in eight patients, seven with IUI (14.3%) and one with ICI (2.0%); the difference is significant at P less than 0.05. The pregnancy rate per treatment cycle was 7.3% versus 1.2% (P less than 0.001). This study supports the use of IUI with processed sperm in the treatment of infertility due to oligoasthenospermia.     

Urinary catechol estrogens in cycles stimulated by human menopausal gonadotropin

Catechol estrogens, estrogen metabolites of potential physiologic significance, were measured in infertile women undergoing ovulation induction with human menopausal gonadotropins. Urinary 2-hydroxyestrone (2-OH-E1) specimens were obtained from 12 women in one or more stimulated cycles. The actual time for the administration of human chorionic gonadotropin to induce ovulation was based on serial plasma estradiol (E2) specimens. A significant correlation between plasma E2 and urinary 2-OH-E1 was demonstrated, similar but more pronounced than that seen in normal cycling women. This confirms previous work that showed that 2-OH-E1 is the major urinary estrogen metabolite in the nonpregnant state and further suggests that urinary catechol estrogens are a useful index of ovarian function.     

Results of ovulation induction using human menopausal gonadotropin or purified follicle-stimulating hormone in hypogonadotropic hypogonadism patients.

OBJECTIVE: To compare ovarian performance and hormonal levels, after ovulation induction, in patients with isolated hypogonadotropic hypogonadism, using two different gonadotropin drugs. DESIGN: Patients were treated during consecutive cycles, using the same stimulation protocol, with human menopausal gonadotropin (hMG) in the first treatment cycle and purified follicle-stimulating hormone (FSH) in the second one. SETTING: Specialist Reproductive Endocrine Unit. PATIENTS, PARTICIPANTS: Nine patients with isolated hypogonadotropic hypogonadism. MAIN OUTCOME MEASURE: Duration of stimulation, number of leading follicles, serum estradiol (E2) concentration and endometrial thickness at the time of human chorionic gonadotropin administration, and the occurrence of ovulation. RESULTS: Compared with hMG, treatment with purified FSH required significantly more ampules of drug (P less than 0.04) but resulted in a significant reduction in the number of leading follicles (P less than 0.05), serum E2 concentrations (P less than 0.002), endometrial thickness (P less than 0.02) and the occurrence of ovulation (P less than 0.05). CONCLUSION: This study in isolated hypogonadotropic hypogonadism patients is consistent with the two-cell two-gonadotropin hypothesis, that both gonadotropins are required to accommodate their synergistic action for appropriate steroidogenesis. In treating this group of patients, the superior efficacy of hMG compared with purified FSH preparation is beyond question.     

Ibuprofen modulation of human chorionic gonadotropin-induced ornithine decarboxylase activity and ovulation in the rabbit ovary

The activity of ornithine decarboxylase, the rate-limiting enzyme in polyamine synthesis, increases as granulosa cells proliferate in developing follicles. Both luteinizing hormone and prostaglandins stimulate ornithine decarboxylase activity. Here, we sought to determine the relative contributions of both trophic stimuli to ornithine decarboxylase activity in the preovulatory rabbit ovary. Baseline ovarian ornithine decarboxylase activity, determined by measuring the release of CO2 from (1-14C)-ornithine, was 13.4 +/- 1.27 (mean +/- SD) pmol of carbon dioxide per hour per milligram of protein. Treatment with ibuprofen, a prostaglandin synthetase inhibitor, led to a significant (p less than 0.05) decrease in the baseline ovarian ornithine decarboxylase activity (4.7 +/- 0.29 pmol of carbon dioxide per hour per milligram of protein). Administration of human chorionic gonadotropin (hCG) (50 IU/kg intramuscularly) to adult rabbits (2.5 to 3.5 kg) elicited a 1,200% elevation of ovarian ornithine decarboxylase activity 5 hours after injection; there was a return to baseline by 11 hours after injection. Stimulation with human chorionic gonadotropin led to ovulation in 22.2%, 25%, and 60% of rabbits at 7, 9, and 11 hours after treatment, respectively. Single-dose ibuprofen treatment (5 mg/kg intramuscularly), 7 hours after human chorionic gonadotropin administration inhibited ovulation and elevated ovarian ornithine decarboxylase activity. These results indicate that ibuprofen effectively inhibits ovulation in hCG-stimulated rabbit ovaries in the presence of a significant (p less than 0.001) elevation in ovarian ornithine decarboxylase activity. Thus, different intracellular mechanisms are involved in the prostaglandin modulation of basal and hCG-stimulated cells during the course of preovulatory follicle maturation.     

Sextuplet pregnancy after human menopausal gonadotropin superovulation and intrauterine insemination. A case report

Sextuplet pregnancy occurred after human menopausal gonadotropin ovulation induction, intrauterine insemination and human chorionic gonadotropin support in the luteal phase. The patient's peak serum estradiol concentration was 861 pg/mL, and ultrasound monitoring demonstrated only one follicle greater than 11 mm in diameter. The possibility of high-order multiple birth exists despite intensive monitoring efforts for this therapy.     

Correlation of ultrasonic and endocrinologic measurements in human menopausal gonadotropin therapy

Ultrasonographic measurement of follicle growth and estradiol concentrations have been shown to correlate well in spontaneous and Clomid-induced ovulatory cycles. However, little is known about these changes during human menopausal gonadotropin (hMG) therapy. Twenty-five women who did not ovulate when treated with clomiphene were treated with hMG during 70 treatment cycles. Eleven patients had withdrawal bleeding after progesterone administration (group 1) and 14 did not bleed (group 2). Follicle growth was monitored with intermittent serum estrogen determinations and daily ovarian ultrasound with an ADR Model 2140 real-time sector scanner. The mean dominant follicle size at the time of human chorionic gonadotropin (hCG) injection was 21.2 mm +/- 0.6 (SEM) and was not different between the two groups. Mean serum estrogen level at the time of hCG injection was 1,121 pg/ml and correlated with follicle volume. At the time of hCG injection in group 2, one dominant follicle was present in 65% and two were present in 35% of the patients. Among those in group 1, two or more dominant follicles were present during all cycles. Mean serum estrogen levels were significantly higher in group 1 patients than those in group 2. This "chemical hyperstimulation" was induced in order to delay ovulation until adequate follicular size had been achieved. All cycles were ovulatory. Five patients in group 1 and eight in group 2 conceived. The use of ultrasound enables the physician to evaluate follicular growth and development daily and thus to individualize treatment and to reduce the need for estrogen monitoring.