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PubMed1987

Clomiphene citrate augments follicle-stimulating hormone-induced luteinizing hormone receptor content in cultured rat granulosa cells.

Although clomiphene citrate (CC) has been widely used for ovulation induction, the mechanism of its pro-fertility effect is not entirely clear. Because CC augments ovarian aromatase activity, the effect of CC on follicle-stimulating hormone (FSH)-induced luteinizing hormone (LH) receptor content was examined in primary cultures of rat granulosa cells. Control cultures contained low LH receptor content, whereas FSH stimulated LH receptor formation in a dose-dependent manner. The concomitant addition of CC enhanced FSH potency as shown by a decrease in the ED50 for FSH by 2.2-fold. Some cells were treated with a low concentration of FSH (12 ng/ml) in the presence or absence of increasing concentrations of CC (10(-8) M to 10(-6) M). The enhancement of FSH-stimulated LH receptor formation was found to be CC dose dependent, with an ED50 of 6 X 10(-8) M. Thus, CC may play a direct ovarian role in the enhancement of FSH-stimulated LH receptors. The gonadal action of this compound may be relevant in understanding the efficacy of CC in ovulation induction.

Animals↗
PubMed1989

Pulsatility of serum-luteinizing hormone during hyperstimulation with clomiphene citrate and human menopausal gonadotropin for in vitro fertilization.

The pulsatile pattern of gonadotropin secretion regulates follicular growth and corpus luteum function in normal cycles, but the role of endogenous gonadotropin pulses in hyperstimulated cycles is unclear. We studied pulsatility of serum-luteinizing hormone (LH) in the late follicular and midluteal phases in four women after hyperstimulation with clomiphene citrate, human menopausal gonadotropin, and human chorionic gonadotropin, and in five women with normal untreated cycles. In the late follicular phase, the number, interval, amplitude, and area of LH pulses did not show significant differences between hyperstimulated and control cycles. In the midluteal phase, the long-lasting (greater than 90 minutes) LH pulses typical for the normal luteal phase, were not found after hyperstimulation. As the length of the luteal phase in these cases was normal, the significance of this finding remained obscure.

Clomiphene↗
PubMed1990

Prediction of individual response to controlled ovarian hyperstimulation by means of a clomiphene citrate challenge test.

A clomiphene citrate (CC) challenge test was carried out in 114 patients to evaluate the capacity of this test to predict the patient's individual response to controlled ovarian hyperstimulation (COH) performed with a gonadotropin-releasing hormone agonist and human menopausal gonadotrophins (hMG) for in vitro fertilization. The sum of follicle-stimulating hormone measured before and after CC intake, is the parameter that correlated best with subsequent response to COH. The upper limit of the reference value for this parameter, established by considering the CC challenge test performed on 26 patients who became pregnant, was 26.03 mIU/mL. Twenty patients who presented a CC challenge test result above the reference value were compared with patients with a normal test result. For these 20 patients, COH required more hMG and was cancelled in 25% of the cases (instead of 1% in the control group). The number of follicles aspirated, oocytes retrieved, and embryos obtained were on average six times lower than in patients with a CC challenge test result within the reference value, and no pregnancy was obtained. We concluded that CC challenge test provides a reliable individual prognosis for the ovarian response to COH.

Clomiphene↗
PubMed1990

Effects of gonadotropin-releasing hormone agonist and clomiphene citrate on estrogen/progesterone-induced hyperprolactinemia in monkeys.

The effects of follicular phase clomiphene citrate (CC) and two regimens of leuprolide acetate on estrogen-progesterone-induced hyperprolactinemia in nonhuman primates were studied. All groups received estradiol (E2) benzoate (12.5 micrograms intramuscularly on cycle days 2 to 33) and progesterone (P) (silastic implant for cycle days 14 to 33). A gonadotropin-releasing hormone agonist (GnRH-a) (Lupron 0.5 mg daily, TAP Pharmaceuticals, Chicago, IL) was administered from cycle day 2 to 14 in group II and from day 20 of the previous cycle until cycle day 14 in group III. Oral CC was given on cycle days 3 through 7 in group IV. No significant differences of mean E2 and P concentrations were noted between groups. Neither GnRH-a nor CC had an overall effect on E2/P-induced hyperprolactinemia. However, for the 5-day interval at the onset of the P treatment there was a significant increase in prolactin (PRL) secretion for group II (130.4 +/- 30.6) versus group I (53.9 +/- 3.3), group III (64.4 +/- 11.1), and group IV (68.8 +/- 14.3). This suggests that leuprolide may exert a delayed stimulatory effect on PRL secretion, or that complete suppression of the putative paracrine regulation of PRL stimulation may require more than 13 days of GnRH-a administration.

Animals↗
PubMed1990

Comparative trial of luteinizing hormone-releasing hormone analog/human menopausal gonadotropin and clomiphene citrate/human menopausal gonadotropin in an assisted conception program.

To establish the usefulness of a new drug regimen in an assisted conception program, a trial was performed comparing clomiphene citrate (CC) plus human menopausal gonadotropins (hMG) with a new regimen of intranasal luteinizing hormone-releasing hormone (LH-RH) analog plus hMG. One hundred two patient cycles received treatment with CC and hMG and 118 patient cycles received treatment with LH-RH analog and hMG. Fifteen percent of cycles were canceled in the CC group and 8% in the analog group. Four percent of cycles in the CC group were canceled due to premature ovulation. The number of oocytes collected in the analog group was significantly higher than in the CC group (8.5 versus 5.5), as was the number of mature oocytes (3.5 versus 2.7). However, the percentage of mature oocytes was higher in the CC group (54.2% versus 42.3%). The number of embryos resulting from in vitro fertilization as well as the number of cleaving embryos were significantly higher in the analog group (5.2 versus 2.8 and 4.6 versus 2.3, respectively). The pregnancy rate in the analog group was significantly higher than in the CC group (30.6% versus 16.1%), as was the live birth rate (21% versus 8%). Early pregnancy loss was significantly higher in the CC group than in the analog group (35% versus 9%); and the serum level of LH on the day of human chorionic gonadotropin (hCG) administration was also significantly elevated in the CC group when compared with the analog group (8.1 versus 4.1).(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Intranasal↗
PubMed1990

Treatment of clomiphene citrate-resistant polycystic ovarian syndrome with pure follicle-stimulating hormone or human menopausal gonadotropin.

Two hundred ten treatment cycles of follicle-stimulating hormone (FSH) or human menopausal gonadotropin (hMG) were completed in 49 patients with clomiphene citrate-resistant polycystic ovarian syndrome. The results from 68 cycles of daily intramuscular (IM) FSH and 41 cycles of IM hMG were compared. The ovulation rate, maximum serum estradiol (E2) levels achieved, and pregnancy rate were similar in both groups, but FSH resulted in significantly fewer follicles developing and hyperstimulation. The 68 cycles of daily IM FSH were further compared with the outcome of administering the FSH as an alternate-day IM injection in 70 cycles, and by subcutaneous pulsatile injection in 31 cycles. There were no differences in any of the parameters measured between daily and alternate-day FSH. Pulsatile FSH required a greater total dose over a longer period of time to achieve stimulation. It also produced fewer follicles, a lower maximum serum E2 level, and the lowest incidence of hyperstimulation. Twenty pregnancies resulted, of which 6 aborted in the first trimester; there was 1 set of twins and 13 singleton pregnancies. The cumulative pregnancy rate after 6 treatment cycles was 62%.

Clomiphene↗
PubMed1990

Intrauterine insemination does and clomiphene citrate does not improve fecundity in couples with infertility due to male or idiopathic factors: a prospective, randomized, controlled study.

In the present prospective study we compared, in terms of pregnancy rates, the differences between intrauterine insemination (IUI) of in vitro capacitated husband's semen and timed natural intercourse in spontaneous or clomiphene citrate (CC) stimulated cycles. A rapid urinary luteinizing hormone peak detection test was used for timing of ovulation. Forty patients suffering from longstanding infertility of male (n = 17), cervical (n = 2), and idiopathic (n = 21) origin were randomly assigned into four distinct treatment modalities during 4 consecutive cycles. A total of 132 cycles were analyzed. In 35 cycles treated with CC plus IUI, five conceptions were achieved, whereas three pregnancies occurred in 32 inseminated spontaneous cycles. Only 1 patient conceived after timed intercourse in 31 CC stimulated cycles, and no pregnancy resulted from 34 spontaneous cycles combined with timed intercourse. There was a statistically significant higher conception rate in cycles in which IUI was performed, whereas the use of CC does not seem to improve the pregnancy rate. Analysis of results for other modifying factors did not substantially affect the relative risk (odds ratio) of pregnancy.

Adult↗
PubMed1990

Evaluation of leuprolide acetate and gonadotropins versus clomiphene citrate and gonadotropins for in vitro fertilization or gamete intrafallopian transfer.

A prospective randomized trial was conducted to compare the efficiency of two ovarian stimulation protocols for in vitro fertilization-embryo transfer or gamete intrafallopian transfer. Protocol 1 consisted of clomiphene citrate and human menopausal gonadotropin (hMG) with 55 cycles of 42 patients being evaluated. Protocol 2 had 38 cycles of 34 patients receiving a gonadotropin-releasing hormone agonist (GnRH-a) and hMG. The incidence of a spontaneous luteinizing hormone surge was 38.2% in protocol 1 and 0% in protocol 2. Both protocols had a similar cancellation rate. The total clinical pregnancy rates per oocyte retrieval for patients receiving protocol 1 and protocol 2 were 19.5% and 10.3%, respectively. The difference was not statistically significant. Therefore, as first-line ovulation induction agents, it cannot be concluded that either protocol demonstrates a clear superiority over the other and further trials of the GnRH-a/hMG combination are indicated.

Adult↗
PubMed1990

Efficacy of clomiphene citrate in the treatment of luteal phase deficiency: quantity versus quality of preovulatory follicles.

We tested the hypothesis that the efficacy of clomiphene citrate (CC) in the treatment of luteal phase defect (LPD) is related more to the number of ovulatory follicles than to the quality of a single follicle. Eighteen ovulatory women with LPD as defined by endometrial biopsies that lagged behind chronological dates by at least 3 days on two separate menstrual cycles were studied. During the menstrual cycle before treatment and also during a treatment cycle (100 mg of CC, on days 5 to 9), we obtained an endometrial biopsy 9 to 12 days after ovulation. All biopsies were read in a blinded fashion by the same gynecological pathologist. During the treatment cycle, 10 women had more than one preovulatory follicle (greater than 15 mm, mean of three dimensions), while 8 had one preovulatory follicle. Luteal phase defect was corrected according to biopsy in 8 of the 10 women with more than one preovulatory follicle, but in only 2 of the 8 women with a single preovulatory follicle.

Adult↗
PubMed1990

Use of buserelin acetate in an in vitro fertilization program: a comparison with classical clomiphene citrate-human menopausal gonadotropin treatment.

A comparison has been established retrospectively between clomiphene citrate-human menopausal gonadotropin (CC-hMG) and buserelin acetate-hMG treatments in in vitro fertilization trials performed over a 3-year period. The analysis of 466 CC-hMG and 319 buserelin acetate-hMG trials shows that buserelin acetate-hMG stimulation generates a greater ovarian response resulting in higher numbers of oocytes being retrieved (6.2 + 3.8 versus 9.3 + 5.2) and fertilized (2.8 + 2.7 versus 4.3 + 3.8). More embryos are thus obtained, allowing a wider choice for intrauterine replacement and cryopreservation. Mean embryonic vitality scores do not differ (4.33 + 1.51 versus 4.44 + 1.54), implying that the embryonic quality remains similar in both treatments. A premature demise of the corpus luteum occurs in a large proportion of buserelin acetate-hMG cycles. However, when suppletive progesterone treatment is given, there is a trend toward a better implantation rate per embryo, and a significantly higher ongoing pregnancy rate is observed in relation to buserelin acetate-hMG treatment (20%) as compared with CC-hMG cycles (14%).

Adult↗
PubMed1990

Luteinizing hormone bioactivity and variable responses to clomiphene citrate in chronic anovulation.

In 18 women with infertility and chronic anovulation with normal gonadotropins, three different responses were observed to increasing doses (250 to 750 mg) of clomiphene citrate (CC). Follicle development and ovulation in 8, follicle development but no ovulation without human chorionic gonadotropin (hCG) in 6, and no response to CC in 4. Serum concentrations of bioactive luteinizing hormone (bioactive-LH), immunoactive (immunoactive-LH), follicle-stimulating hormone, and estradiol (E2) were measured and follicle growth was assessed by daily ultrasound. Findings were compared with 8 normal ovulatory controls. Folliculogenesis on CC therapy, based on our data, was 78%; however, only 44% ovulated spontaneously, 34% required hCG for follicle rupture. There were no apparent hormonal indicators to predict responders from nonresponders. The absence of an LH surge in the presence of follicles and sustained high E2 concentrations in 34% of patients may be associated with a decreased E2 sensitivity at the hypothalamic-pituitary level. Ultrasound easily identified patients who responded to CC with folliculogenesis but did not initiate an LH surge. Follicle rupture was achieved promptly by hCG administration.

Adult↗
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

The relative success of gonadotropin-releasing hormone analogue, clomiphene citrate, and gonadotropin in 1,099 cycles of in vitro fertilization.

OBJECTIVES: To evaluate the effectiveness of and analyze the factors influencing the outcome of three ovarian stimulation protocols used during in vitro fertilization (IVF) in a large population. DESIGN: Retrospective file review. SETTING: In vitro fertilization program in one center during the years 1985 to 1990. PATIENTS AND PROTOCOLS: Three hundred forty-one patients received clomiphene citrate (CC) and human menopausal gonadotropin (hMG), 365 received hMG alone, and 393 received gonadotropin-releasing hormone analogue (GnRH-a) for pituitary suppression followed by hMG stimulation. MAIN OUTCOME MEASURE: Rates of cancellation, total pregnancies, and ongoing pregnancies, with breakdown by age of patients. RESULTS: The cancellation rate because of early luteinization following GnRH-a/hMG was significantly reduced compared with the other two protocols: 3.6% versus 9.4% and 13.7% for CC/hMG and hMG, respectively. However, in women over 40 years of age, GnRH-a/hMG resulted in the highest rate of poor ovarian response. Significantly more oocytes were retrieved, fertilized, and cleaved after the use of GnRH-a/hMG compared with the other two protocols. Despite this, clinical pregnancy rate (PR) was the highest with CC/hMG compared with GnRH-a/hMG and hMG:31.4% versus 16.9% and 15.7%, respectively. Ongoing PRs were 20.5%, 9.7%, and 11.6%, respectively. CONCLUSIONS: Although the use of GnRH-a for pituitary suppression before ovarian stimulation for IVF reduced the cancellation rate and increased the number of retrieved oocytes, it was not found to result in higher PRs than those achieved by stimulation with CC/hMG. This suggests that treatment by GnRH-a/hMG should be reserved mainly for the prevention of early luteinization.

Clomiphene↗
PubMed1993

The effect of clomiphene citrate treatment on cervical mucus and plasma estradiol and progesterone levels.

OBJECTIVES: To study the relationship between cervical mucus (CM) quality, postcoital test (PCT) results and plasma estradiol (E2) in clomiphene citrate (CC)-treated women. A subsidiary aim was to study the relationship between CM quality and plasma progesterone (P). DESIGN: Untreated women were compared with oligo-ovulatory patients given CC. SETTING: Infertility Clinic, Fazakerley Hospital, United Kingdom. PATIENTS, PARTICIPANTS: Fifty-one untreated patients and 31 women given CC. INTERVENTIONS: The treated women were given 50 mg/d CC from days 2 to 6 of their cycle. MAIN OUTCOME MEASURES: A CM assessment, a PCT, plasma E2, and P were performed at the anticipated time of ovulation based on at least two previous basal body temperature charts and menstrual patterns. RESULTS: In untreated women there was a very strong tendency for CM quality to improve with rising plasma E2 levels and to worsen with rising plasma P levels. There was a significant association between CM quality and PCT results. Similar results were found in CC-treated women, except that plasma E2 was very significantly higher and there was a significant inverse relationship between plasma E2 and CM quality. CONCLUSION: High plasma E2 in the periovulatory phase in CC-treated women is a marker for increased sensitivity to and continuing action of the antiestrogen. This impairs the quality of the CM.

Cervix Mucus↗
PubMed1993

Relationship of endometrial thickness and pattern to fecundity in ovulation induction cycles: effect of clomiphene citrate alone and with human menopausal gonadotropin.

OBJECTIVE: To determine if preovulation endometrial thickness or pattern are related to fecundity and to use of clomiphene citrate (CC) or hMG in IUI. DESIGN: Prospective ultrasound evaluation the day of hCG after CC alone (n = 197), hMG alone (n = 49), concurrent hMG or sequential CC and hMG (n = 205), and no medications (n = 23). SETTING: Private fertility clinic. PATIENTS: Two hundred seventy-one patients undergoing 474 cycles of IUI. MAIN OUTCOME MEASURES: Endometrial thickness, pattern, per cycle fecundity, and continuing pregnancy. RESULTS: Endometrial thickness was related to fecundity and continuing pregnancy. No pregnancies occurred when thickness was < 6 mm. The continuing pregnancy rate was 12.6% when thickness was > or = 9 mm, compared with 6.9% when thickness was 6 mm to 8 mm. Endometrial pattern was unrelated to pregnancy. Average endometrial thickness was decreased when hMG and CC were used in combination (7.9 mm) compared with hMG alone (9.4 mm). Endometrial thickness was negatively related to CC dose and positively related to the day of hCG administration by ANOVA. CONCLUSIONS: Endometrial thickness the day of hCG administration is prognostic of fecundity and continuing pregnancy in cycles of ovulation induction.

Adult↗
PubMed1993

Clomiphene citrate affects cervical mucus and endometrial morphology independently of the changes in plasma hormonal levels induced by multiple follicular recruitment.

OBJECTIVE: To analyze the effects of clomiphene citrate (CC) on cervical mucus (CM) and endometrial morphology independently of hormonal changes encountered when CC is administered for ovulation induction. DESIGN: Volunteers whose ovarian functions were temporarily suppressed (n = 18) by a long-acting GnRH agonist and 6 women of similar age suffering from premature ovarian failure (POF) received E2 and P. Half of the women also received CC (50 mg/d, days 2 to 6). SETTING: Tertiary University Institution, Hôpital A. Béclère. PATIENTS, PARTICIPANTS: Eighteen volunteers suffering from infertility not related to a uterine cause and 6 women of similar age suffering from POF. MAIN OUTCOME MEASURE: Plasma gonadotropins, E2, and P were measured at baseline to confirm that the ovaries were inactive and twice weekly during physiological E2 and P replacement. Cervical mucus was analyzed on day 14 and scored from 0 to 15. Endometrial biopsies were obtained on replacement days 20 and 24 for conventional histology and immunocytochemistry analysis of estrogen receptors and progesterone receptors (PR). Premature ovarian failure women whose results have been previously published served as controls for day 20 biopsies. RESULTS: Cervical mucus scored lower in women who received CC (5.5 +/- 3.2) than in controls (13.6 +/- 4.7, mean +/- SEM). On day 20, endometrial findings were similar in women treated with CC and in controls. On day 24, specimens showed a significant delay in endometrial maturation in women treated with CC. On day 24, only staining for PR selectively persisted in endometrial stroma, and no difference was observed between women who received CC and controls. CONCLUSION: Our results indicate that CC significantly alters CM quality and late luteal phase endometrial morphology despite physiological levels of plasma E2 and P. Hence, clinicians should monitor E2 levels when using CC, and caution should be exerted when supraphysiological levels of E2 are not present to counterbalance the effects of CC on the CM and the endometrium.

Adult↗
PubMed1993

Serum levels of insulin-like growth factor binding protein-1 and ovulatory responses to clomiphene citrate in women with polycystic ovarian disease.

OBJECTIVE: To study the serum levels of insulin, insulin-like growth factor I (IGF-I), and insulin-like growth factor binding protein-1 (IGFBP-1) in relation to clomiphene citrate (CC) responsiveness in women with polycystic ovarian disease (PCOD). DESIGN: Prospective. PATIENTS, SETTING: Twenty-three women with PCOD admitted consecutively to the University Infertility Clinic, a tertiary referral center. INTERVENTIONS: Blood samples were taken at fasting state and during oral glucose tolerance test (OGTT) for the determination of insulin, IGF-I, and IGFBP-1. A dose of 50 to 200 mg/d CC was given for ovulation induction. RESULTS: With CC treatment, ovulation was achieved in 13 of 23 PCOD patients. The IGFBP-1 concentration was lower in CC nonresponders than in CC responders (20.5 +/- 4.0 ng/mL versus 41.0 +/- 8.5 ng/mL) (P < 0.05). This difference was accentuated in 13 lean PCOD patients. Lean CC nonresponders (n = 7) had almost threefold lower serum IGFBP-1 levels than lean CC responders (n = 6) (24.0 +/- 3.1 ng/mL versus 61.8 +/- 8.6 ng/mL) (P < 0.01). By contrast, among 10 obese PCOD patients, the IGFBP-1 levels were low irrespective of CC responsiveness (14.8 +/- 8.0 ng/mL versus 16.7 +/- 7.2 ng/mL). The differences remained during OGTT. The concentrations of IGF-I, insulin, sex hormone-binding globulin, LH, FSH, and androgens showed no significant differences between CC responders and nonresponders. There was an inverse correlation between serum insulin and IGFBP-1 levels in obese PCOD patients, whereas this was not seen in lean patients. CONCLUSION: In lean PCOD patients, low serum IGFBP-1 concentration is related to CC unresponsiveness by a mechanism unrelated to insulin.

Adult↗
PubMed1993

Evaluation of the significance of the estradiol response during the clomiphene citrate challenge test.

OBJECTIVE: To evaluate the relationship between the E2 response during the clomiphene citrate (CC) challenge test and ovarian responsiveness to exogenous gonadotropins. DESIGN: Performance of a CC challenge test followed by ovulation induction with exogenous gonadotropins as part of participation in an assisted reproduction program. SETTING: Assisted reproduction program in a large military tertiary care center. PATIENTS: Two hundred forty-seven women between the ages of 24 and 39 years with normal CC challenge tests within 1 year of their assisted reproduction cycle. INTERVENTIONS: Performance of CC challenge tests and ovulation induction with exogenous gonadotropins as a component of an assisted reproduction cycle. MAIN OUTCOME MEASURES: Correlation of the E2 response during the CC challenge test and peak E2, the duration of stimulation, number of ampules of exogenous gonadotropins, number of mature follicles, number of mature oocytes recovered, and fertilization and pregnancy rates in an assisted reproduction program. RESULTS: No correlation exists between the E2 response during the CC challenge test and any of the parameters evaluated. CONCLUSION: Monitoring of the E2 response during the CC challenge test did not predict ovarian responsiveness or pregnancy rates in patients participating in an assisted reproduction program and one may choose not to include it in routine testing.

Adult↗