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[Clomiphene-exposed pregnancies--analysis of 39 information requests including 25 cases with known outcome].

With the up to date published data, the risk of clomiphene exposure during pregnancy cannot be determined. After a review of animal experimentation results, we will discuss the human data. Most of the publications with human exposition concern treatments given before the beginning of pregnancy. The questions addressed to the Centre de Pharmacovigilance of Paris F. Widal will be detailed. From May 1983 to July 1995 39 requests are available with only 25 cases of known outcomes. For these 25 cases, five elective terminations and three spontaneous abortions are reported. Only one defect was observed among the 17 births (9 females, 8 males): unilateral fibula agenesis the imputability of which is difficult to establish. These data seems reassuring; however, the number of patients studied is small. Other studies on clomiphene-exposed pregnancies are necessary in order to investigate this risk.

Abnormalities, Drug-Induced↗

Clomiphene citrate-resistant polycystic ovary syndrome. Preventing multifollicular development.

OBJECTIVE: To determine the efficiency and comparison of two different protocols, human menopausal gonadotropin (hMG) plus gonadotropin-releasing hormone analog (GnRH-a) and low-dose hMG to reduce multifollicular development in clomiphene-resistant polycystic ovary syndrome (PCOS) patients. STUDY DESIGN: Prospective comparative and pilot study in 20 patients for 31 cycles. The first group (n = 10) was treated with buserelin acetate, 600 micrograms/d, for six weeks before ovulation induction with hMG in conventional doses for 14 cycles. The other group (n = 10) was treated only with low-dose hMG for 17 cycles. All cycles were compared in terms of the number of follicles per cycle, cycles human chorionic gonadotropin withheld, estradiol level on ovulation day, treatment duration and number of ampules used per cycle. In addition, the outcome of cycles and complications of multifollicular development, ovarian hyperstimulation syndrome (OHSS) and multiple pregnancy were determined. RESULTS: As compared with the GnRH-a + hMG protocol, the low-dose hMG protocol yielded less multifollicular (57.1% vs. 17.6%) and more monofollicular (35.7% vs. 70.6%) development. Consequently, less OHSS (21.4% vs. 0%) and multiple pregnancy (10% vs. 0%) occurred in the low-dose group. CONCLUSION: Low-dose hMG therapy has distinct advantages in eliminating multifollicular development and related complications in clomiphene citrate-resistant PCOS patients. The addition of GnRH-a to gonadotropins does not change the incidence of multifollicular development.

Adult↗

Clomiphene citrate challenge test: cycle to cycle variability of cycle day 10 follicle stimulating hormone level.

The clomiphene citrate challenge test (CCCT), a means of assessing ovarian reserve, was shown by several studies to have an excellent predictive value for achieving conception in natural cycles, during ovulation induction and in-vitro fertilization cycles. Accordingly we elected to study the cycle to cycle variability of CCCT so as to determine the reliability of a single CCCT result. Two groups of patients were studied, the first (n = 40) were those patients who were performing the test because it was indicated, and the second (n = 24) were those who were receiving clomiphene citrate for ovulation induction. In both groups CCCT intercycle variability was significant in 75% of the cases, but this variability altered the prognostic values of the test in only 40% of the first group. In conclusion, our study showed a high percentage of intercycle variability of CCCT but further studies are needed to evaluate the influence of this variability on potential conception.

Adult↗

Outcome of pregnancy after clomiphene therapy.

Of 159 pregnancies conceived after clomiphene therapy, 141 ended in childbirth, including seven sets of twins. There was a probable increase in the number of infants born with major malformations. These were exclusively to women who had not previously borne a normal infant. The incidence of malformed infants compares well with that published after gonadotropin therapy. The possibly higher incidence of malformations seen after drug-induced ovulation would therefore seem to be due to the underlying subfertility state and thus not a direct drug effect.

Abnormalities, Drug-Induced↗

An economic evaluation of laparoscopic ovarian diathermy versus gonadotrophin therapy for women with clomiphene citrate-resistant polycystic ovarian syndrome.

PURPOSE OF REVIEW: Women with polycystic ovarian syndrome are typically anovulatory and require ovulation induction. Ovarian wedge resection was the first treatment for anovulation but was eventually abandoned because of the increased risk of postsurgical adhesions and as medical ovulation induction with clomiphene and gonadotrophins was introduced. However, with the advent of laparoscopy, there has been a return to surgical approaches. The potential advantages of laparoscopic surgery include avoidance of hyperstimulation and the lowered costs make ovarian surgery an attractive alternative to gonadotrophins. RECENT FINDINGS: Clinical trials in New Zealand and the Netherlands have compared costs of laparoscopic ovarian drilling with gonadotrophins. The total cost of treatment in the Netherlands study for the ovarian drilling group was euro 4664 and for the gonadotrophins group was euro 5418. Without the cost of monitoring and the diagnostic laparoscopy then the difference was euro 2110 in favour of ovarian drilling. It was estimated that the cost per term pregnancy would be euro 14,489 for gonadotrophin and euro 11,301 for ovarian drilling (22% lower). The higher rates of multiple pregnancy in the gonadotrophin group were considered to be responsible for the increased costs. In the New Zealand trial the costs of a live birth were one-third lower in the group that underwent laparoscopic ovarian diathermy compared with those women who received gonadotrophins (NZ$19,640 and 29,836, respectively). SUMMARY: Treating women with clomiphene-resistant polycystic ovarian syndrome with laparoscopic ovarian diathermy results in reduced direct and indirect costs. The reduction in multiple pregnancies makes the alternative of surgery particularly attractive.

Cost-Benefit Analysis↗

Effect of clomiphene citrate on PMSG-induced ovulation in the immature rat.

The dose of 15 IU PMSG was found to be optimal for inducing ovulation within 74 hours in 27-day-old immature female rats. There was a significant decrease in the mean number of ova per ovulating animal when the dose was raised beyond this (r = 0.6554, p less than 0.001 for the range from 15 to 100 IU), but the number of ovulating animals did not decrease unless more than 80 IU PMSG were injected. The PMSG-induced ovulation was not affected by treating the animals with 10 or 100 mug clomiphene citrate at 0, 24, 48, 54, 60, 66 hours or at 0, 24, and 48 hours.

Age Factors↗

Clomiphene citrate in the management of infertility associated with shortened luteal phases.

Repetitively short luteal phases were found in eight infertile women. The short luteal phase was defined as 10 days or less from the presumed time of ovulation (as assessed by basal body temperature recording) to the onset of menses. Clomiphene citrate (Clomid) therapy resulted in pregnancy in two patients and lengthened the luteal phase in the other six. Ultimately, seven of eight patients conceived during Clomid therapy. Clomid therapy can lengthen the luteal phase in patients with luteal temperature elevation of 10 days or less. The occurrence of short luteal phases may be associated with infertility.

Anovulation↗

[Combined intra-uterine and ectopic pregnancy following the treatment with clomiphen (author's transl)].

Report on a case of combined pregnancy in a 25 year old patient who was treated with Clomiphen for anovulatory cycles. The left tubal pregnancy was removed at 12 weeks gestation. The intra-uterine pregnancy resulted in a term delivery of a 3 kg. 670 g. normal infant. Combined pregnancies rarely occur without treatment with ovulation inducing agents by superfecundation and superfetation. Ovulation inducing agents increase the theoretical possibility of combined pregnancy. Obstetricians should be alert to the possibility of combined pregnancy following induction of ovulation.

Adult↗

Induction of ovulation by clomiphene citrate in the Indian vespertilionid bat, Scotophilus heathi.

The ovulation induction property of clomiphene citrate (CC) and human chorionic gonadotropin (hCG) was studied in Scotophilius heathi, an Indian tropical vespertilionid bat, during the period of delayed ovulation between December to early January. The results of the study showed that 10 microg of CC alone was ineffective to induce ovulation, whereas 100 microg CC and 10 IU hCG alone induced ovulation. A significant (P < 0.01) increase in the ovulation rate was observed when 10 microg CC followed by 10 IU hCG, compared to 10 IU hCG and 100 microg CC alone groups. Finally, CC at a 100 microg dose, followed by 10 IU hCG, produced superovulation (14.00 +/- 0. 70), which is significantly different in comparison to all other groups. This is the first report of ovulation induced by CC in the Indian tropical bat as well as in any animal model that exhibits temporary anovulation similar to polycystic ovary syndrome (PCOD) during the normal physiology of reproduction.

Animals↗

Clomiphene citrate and human chorionic gonadotropin in the treatment of anovulatory infertility.

Fifty-one patients with proven anovulatory infertility were treated for four months. For two months each, a dose regimen of 50 mg of clomiphene citrate daily for five days and one of 150 mg daily for five days was prescribed. During one month of each of these two regimens, each patient also received 5000 IU of human chorionic gonadotropin intramuscularly. Thirty-three of the 51 patients ovulated at least once during the four months of treatment; the ovulation rate was 64.7%. Sixteen pregnancies occurred during the treatment, for a pregnancy rate of 31.4%. Human chorionic gonadotropin did not appear to increase the ovulation rate.

Anovulation↗

Effect of clomiphene citrate on the rabbit ovary.

The effect of clomiphene citrate on the rabbit ovary was studied in mature nulliparous rabbits pretreated with three consecutive doses ranging from 0.01-10.0 mg/kg per day. With increasing doses a trend of decrease in mean ovarian weight (mg/kg body weight) is observed 2 days after termination of treatment. Five days later a significant increase occurs, which then subsides again to control values on day 12 after termination of treatment. During this period, no matings or injections of luteinizing hormone were performed to trigger ovulation; consequently no ovulations are observed. Folliculogenesis appears as normally; number and morphology of follicles are within normal ranges. No endogenous, spontaneous gonadotropin surges are detected in blood serum up to the 7th day after termination of treatment (2 and 10 mg doses). The surface epithelium of the ovary resembles normal germinal epithelium; however, after treatment with high doses a "secretory"-like activity is observed, accompanied with ultrastructural changes.

Animals↗

Preovulatory serum estradiol-17 beta values and ultrasound scans in 17 pregnancies which followed in vitro fertilization and embryo transfer after treatment with clomiphene and hCG.

17 patients whom we treated with clomiphene and hCG became pregnant after in vitro fertilization (IVF) and embryo transfer (ET). We now report on our experience with preovulatory estradiol 17 beta values and ultrasonography in determining the time of hCG administration in these patients. The mean estradiol value just before the hCG injection was 329 +/- 75 pg/ml/follicle. The mean follicle diameter on ultrasound was 23.4 +/- 1.5 mm on the same day. In four cases, we only used estradiol values and in one case only ultrasound for the timing of the hCG injection. Both methods of monitoring follicular growth are discussed.

Adult↗

Effects of trans-clomiphene in combination with AY-9944 on rat CNS morphology and biochemistry.

Developing rats were injected intraperitoneally twice weekly with a combination of two hypocholesterolemic agents: trans-clomiphene 50 mg per kg body weight, and AY-9944, 5 mg per kg body weight. Treatment was initiated at 5 days of age. Biochemical and electron microscopic examination was carried out on animals sacrificed at 20 days of age. Only rarely were cytoplasmic inclusion bodies seen in the CNS. Biochemical analysis of the brain and spinal cords of treated animals indicated the abnormal accumulation of three sterols, zymosterol (5alpha-cholesta-8,24-dien-3beta-ol), 7-dehydrocholesterol (cholesta-5,7-dien-3beta-ol) and 7-dehydrodesmosterol (cholesta-5,7,24-trien-3beta-ol). The 7-dehydrosterols constituted from 56--66% of the total CNS sterol component. Zymosterol was a relatively minor (2.4--5.0%) component.

Animals↗

Combined clomiphene citrate (CC) and human menopausal gonadotropins (hMG) in a fixed schedule for follicular recruitment during in vitro fertilization: effects on premature luteinizing hormone (LH) surges.

Recognizing the association between plasma progesterone (P) and an imminent LH surge, we investigated the frequency of P elevation in our stimulation protocol (clomiphene citrate-human menopausal gonadotropins). P was measured retrospectively on the day before, the day of, and the day after human chorionic gonadotropin hCG administration. The means +/- 2 standard deviations for P were as follows: day before hCG, 0.58 +/- 0.86; day of hCG, 0.64 +/- 0.56; and day after hCG, 1.47 +/- 1.22. Seven patients (8%) had P levels greater than 2 SD above the mean. Significant P elevations prior to hCG are infrequent with this protocol, and in the few patients with raised P a trend toward lowered fertilization was noted. The low incidence of P elevation may be secondary to the administration of hCG in a timely manner on the sixth day of estradiol (E2) rise.

Chorionic Gonadotropin↗

The occurrence of ectopic pregnancy with and without clomiphene citrate use in assisted and nonassisted reproductive technology.

An eleven-year review of treatment records of patients who became pregnant as a result of infertility treatment (n = 3692) was conducted. All records were examined to determine whether clomiphene citrate (CC) was used in the cycle of conception and whether or not an ectopic pregnancy occurred. Data were additionally analyzed for the incidence of ectopic pregnancy with and without assisted reproductive technology (ART). The incidence of ectopic pregnancy was similar between CC (3.4%) and non-CC (3.4%) treatment groups receiving non-ART treatment. For non-ART treatments, tubal disease and severe endometriosis resulted in an increase in ectopic pregnancies independent of CC use. The incidence of ectopic pregnancy in patients receiving CC + human menopausal gonadotropin (hMG) for in vitro fertilization (5.4%) and gamete intrafallopian transfer (3.1%) was similar compared to ART treatments with hMG alone. The incidence of ectopic pregnancy was more closely associated with infertility diagnosis rather than CC use.

Adult↗

Antiestrogenic effect of clomiphene citrate in a multiple follicular stimulation protocol.

End-organ antiestrogenic effects of clomiphene citrate (CC) have been demonstrated in the female reproductive tract at the levels of the ovary, cervix, and endometrium. However, it has not been established whether this effect is manifested during concomitant human menopausal gonadotropin (hMG) administration, as occurs in hMG/CC stimulations of multiple follicular development. To assess this question a review was made of serum estradiol (E2) and cervical mucus in 47 hMG and 56 hMG/CC stimulations on days -2, -1, 0, and +1 relative to the day of hCG administration. E2 levels (pg/ml) were significantly lower in the hMG as compared to the hMG/CC group. However, comparing the hMG and hMG/CC groups, cervical mucus scores were significantly higher in the former. Furthermore, an analysis of covariance demonstrated that the cervical mucus scores on each day were significantly lower in the hMG/CC group (P less than 0.001). Thus, in hMG/CC stimulations for in vitro fertilization (IVF), despite the concomitant administration of pharmacologic doses of hMG, CC exerts an antiestrogenic effect on at least one end organ, cervical mucus production. Potentially, this antiestrogenic effect in IVF stimulations would be exerted at other female reproductive tract sites including the endometrium; however, its clinical significance, if any, is unclear.

Cervix Mucus↗

Combination clomiphene citrate/human menopausal gonadotropin stimulation protocols for in vitro fertilization-embryo transfer.

Various protocols have been utilized for stimulation of multiple ovarian follicles in patients undergoing in vitro fertilization-embryo transfer (IVF-ET). Previous studies have suggested that the combination of clomiphene citrate (CC) and human menopausal gonadotropins (hMG) is superior to either CC or hMG alone in terms of follicular development, oocyte recovery, and embryo transfer. However, no significant increase in viable pregnancy rates has been reported with any of the protocols. This report examines five different CC/hMG protocols. While differences were seen in terms of serum estradiol response and fertilization rates of mature oocytes among the various protocols, no significant differences were found in terms of follicular development, oocyte recovery, embryo transfer, or pregnancy. The pregnancy rate in IVF-ET appears unaffected by variations in the dose and timing of CC and hMG in a combination protocol.

Adult↗

DNA synthesis in the pituitary gland of the rat: effect of sulpiride and clomiphene.

Sulpiride administration to rats releases prolactin and increases DNA replication in the anterior pituitary gland. Clomiphene prevents the stimulation of DNA synthesis produced by sulpiride, but does not affect prolactin release from the gland. These findings suggest that the intracellular prolactin content of the anterior pituitary gland plays a role in the regulation of DNA synthesis through a mechanism mediated by oestrogens.

Animals↗