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<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.     

Effects of clomiphene citrate on cytosolic estradiol and progesterone receptor concentrations in secretory endometrium

Cytosolic estradiol and progesterone receptor concentrations were measured in luteal phase endometrial biopsy samples obtained from 12 anovulatory or oligoovulatory women on clomiphene citrate therapy and from 40 normal control subjects. Clomiphene citrate treatment (250 to 750 mg per cycle) decreased both endometrial estradiol and progesterone receptor concentrations. Estradiol receptor levels were nondetectable in seven tissue samples and progesterone receptor levels in four samples from the 12 subjects given clomiphene citrate compared to nondetectable estradiol receptor concentrations in one tissue sample and progesterone receptor concentrations in two samples from the 40 normal control subjects. In histologically dated endometrium, mean estradiol receptor concentrations on days 20 to 23 and progesterone receptor levels on days to 24 to 27 were lower than the values observed in the comparable dated endometrium of normal ovulatory women. Steroid receptor concentrations correlated negatively with the duration of clomiphene citrate therapy, which implies a time-dependent suppressive effect of clomiphene citrate on measurable cytosolic estradiol and progesterone receptor concentrations during the luteal phase of the cycle.     

Monitoring plasma concentrations to individualize treatment with clomiphene citrate

OBJECTIVE: Recent reports have indicated that a number of individual patient characteristics are responsible for the success or failure of clomiphene citrate treatment. However, a priori individualization of doses in different patients has not been investigated. We examined the thesis that wide variability in the metabolism of the active component (zuclomiphene) contributes to variability in response. METHODS: The dose-response relationship of clomiphene was established from a meta-analysis of data from 13 published reports. Limited data relating plasma drug concentrations to treatment outcome were examined to determine whether insufficient systemic exposure at a fixed dosage might contribute to therapeutic failure. RESULTS: A fixed-dosage regimen of 50 mg clomiphene per day is likely to cause ovulation in only 46% of patients; subsequent increment in dosage increases the number of responders but at the expense of considerable delay in individualization of treatment. Case reports indicated that dosage based on plasma drug concentration monitoring could improve patient management, and an algorithm is proposed to facilitate treatment. CONCLUSIONS: Prospective studies of clomiphene citrate should be performed to confirm the hypothesis that the monitoring of plasma zuclomiphene concentrations can significantly accelerate dose individualization and improve the therapeutic outcome with this "orphan" drug.     

Endometrial development was improved by transdermal estradiol in patients treated with clomiphene citrate.

The objective of this study was to examine the effect of transdermal estrogen therapy on the endometrial thickness and serum hormone levels in anovulatory patients treated with clomiphene citrate (CC). There was a significant difference in endometrial thickness between the CC + transdermal estrogen group and the CC only group from day -2 to day +2. Serum estradiol (E2) levels in the CC + transdermal estrogen group were significantly higher than those in the CC only group on day -2 and day 0. Our results support that addition of transdermal E2 to the treatment protocol of the women treated with CC elicited a favorable response of the endometrium.     

小剂量补佳乐在诱导排卵中对子宫内膜发育的影响

目的探讨小剂量补佳乐是否能改善克罗米芬诱导排卵中的子宫内膜发育。方法45例不明原因或男方因素的不育妇女分为三组，自然周期组、克罗米芬组(CC组)、克罗米芬 补佳乐组(CC PGV组)各15例，观察三组hCG日及hCG 9d激素环境、子宫内膜厚度、子宫动脉搏动指数(PI)，hCG日子宫内膜类型。结果CC组无论hCG日还是hCG 9d内膜厚度均明显小于自然周期组，而CC PGV组内膜厚度均明显大于CC组。CC组和CC PGV组子宫动脉PI无显著差别，但均显著大于自然周期组。结论小剂量补佳乐能改善克罗米芬诱导排卵中子宫内膜的发育。     

Direct ovarian effect of clomiphene citrate in the rabbit

The effects of clomiphene citrate (CC) on ovulation and ovum maturation were studied using the isolated perfused rabbit ovary. CC (10(-5) M) added to the perfusate with human chorionic gonadotropin (50 IU) did not affect ovulatory efficiency, ovulation time, oocyte maturation, or degeneration of ovulated ova and follicular oocytes. During perfusion without human chorionic gonadotropin, the percentage of follicular oocytes with germinal vesicle breakdown was significantly increased in response to CC (10(-5) M or 10(-7) M); a greater percentage of follicular oocytes was degenerated. Estradiol (100 ng/ml) added to the perfusate reversed the effect of CC on degeneration of follicular oocytes. Of follicular oocytes from ovaries perfused with CC, 79.3% were degenerated; in contrast, 25% were degenerated in ovaries treated with CC plus estradiol. These data suggest that CC has a direct ovarian effect and that ovum degeneration associated with CC may be related to an antiestrogenic action.     

二甲双胍治疗耐克罗米酚多囊卵巢综合征23例临床分析

目的探讨二甲双胍在多囊卵巢综合征(PCOS)治疗中的作用.方法对23例耐克罗米酚PCOS患者的临床资料进行回顾性分析,比较二甲双胍治疗前后各项内分泌代谢指标的变化及其对恢复月经、促排结局及妊娠的影响.结果二甲双胍治疗前后比较,血清睾酮、空腹胰岛素水平下降,胰岛素敏感性指数上升(P<0.01).6例(26.09%)的患者恢复月经,4例(17.39%)恢复自然排卵,2例妊娠. 二甲双胍加促排治疗共26个周期,排卵周期率为61.54%(16/26),妊娠周期率为23.08%(6/26). 结论二甲双胍可以降低雄激素水平及胰岛素水平,改善PCOS妇女对克罗米酚促排的反应.     

Antiestrogenic action of high-dose clomiphene in primates pituitary augmentation but with ovarian attenuation

Since the dominant follicle is selected by days 5 to 7 of the menstrual cycle, we assessed the differential effects of high-dose clomiphene (25 mg daily) by giving 5-day courses either before (days 1 to 5), during (days 5 to 9), or after (days 9 to 13) emergence of the selected dominant follicle in monkeys. Peripheral sera were obtained daily and assayed for follicle-stimulating hormone (FSH), luteinizing hormone (LH), 17 beta-estradiol (E2), and progesterone (P); serial laparoscopies were performed. Rather than enhancement of gonadotropin-dependent folliculogenesis during clomiphene treatment cycles, ovulation was delayed in 18 of 18 treatment cycles. Interestingly, the interval from treatment to next ovulation lengthened when clomiphene was given in the late follicular phase. Consistently, the clomiphene treatment cycles were characterized by a marked decline of the serum E2 during the 5 days of therapy, despite concurrent elevations of pituitary gonadotropins in circulation, especially FSH. These data suggest that a direct antiestrogenic effect of clomiphene imparted ovarian refractoriness to the prevailing, even enhanced, gonadotropin levels. The vulnerability of follicular maturation to these attenuating effects of clomiphene was greatest in the late follicular phase, well after the dominant follicle had been selected. Even after this clomiphene-induced ovarian hiatus and eventual resumption of new follicle growth, the initial apparent ovulation led to latent, severe corpus luteum insufficiency.     

Effect of clomiphene citrate on serum prolactin in infertile women with ovarian dysfunction.

Serum prolactin (PRL) levels were determined by radioimmunoassay in 12 normal, menstruating women and in 26 infetile women with ovarian dysfunction for one cycle or for about 30 days in amenorrheic women. Galactorrhea was not observed. No significant change in serum PRL levels was observed throughout the normal, menstrual cycle. Of the 26 patients with ovarian dysfunction, seven showed PRL levels higher than normal. Twelve of the 26 patients were treated with clomiphene citrate (Clomid), 100 mg, daily for 5 days. Ovulation occurred in seven, and pregnancy was achi-ved in two of them. Serum PR;, follicle-stimulating hormone, and luteinizing hormone were measured for a preceding control cycle and during the cycle following Clomid treatment in the 12 patients. The serum PRL levels were normal during the control cycle in five of the patients who ovulated with Clomid and high in four patients who failed to ovulate. Although serum PRL levels were not significantly changed by Clomid in the patients who ovulated with the drug, they were markedly decreased during and immediately after Clomid treatment in patients who failed to ovulate with Clomid.     

Mild stimulation with clomiphene citrate in combination with recombinant follicle-stimulating hormone and gonadotropin-releasing hormone antagonist and its influence on serum estradiol level and pregnancy rate

Aim:  The mild ovarian stimulation protocol for in vitro fertilization (IVF) is carried out to minimize adverse side-effects as well as cost. While performing mild ovarian stimulation with a gonadotropin-releasing hormone (GnRH) antagonist, the pregnancy rate was examined in cases that exhibited a serum estradiol (E2) drop down.
Methods:  In this study, 174 patients who requested mild ovarian stimulation for IVF began clomiphene citrate on day 3 and recombinant follicle-stimulating hormone (FSH) on day 5 of their menstrual cycles. A GnRH antagonist was administered when the dominant follicle reached a diameter of 14 mm. Serum luteinizing hormone and estradiol were measured at the time of GnRH antagonist administration and at the time of human chorionic gonadotropin (hCG) injection. Pregnancy rates and implantation rates were compared between 24 cycles in which the E2 level fell at the time of hCG injection and 150 cycles in which it did not fall.
Results:  The pregnancy rate in the cases in which the E2 level fell (25% decrease) at the time of hCG injection was significantly lower than it was in the cases in which it did not fall (16.7 vs 41.0%). The implantation rate for the cases in which the E2 level fell was also lower than that of the control group (7.0 vs 31.0%). There was no significant difference in the number of good-quality embryos between the two groups.
Conclusion:  When performing the mild ovarian stimulation protocol, serum E2 should be followed. It is prudent to avoid embryo transfer in the same cycle in cases that exhibit E2 drop down. (Reprod Med Biol 2008; 7 : 85–89)     

Low dose of ethinyl estradiol can reverse the antiestrogenic effects of clomiphene citrate on endometrium

Fifty healthy, voluntary patients aged between 20 and 30 years with regular menstruation and plasmatic progesterone level >10 ng/ml at the midluteal phase have been enrolled in this study. They were randomly treated with clomiphene citrate (CC; group A) or CC + ethinyl estradiol (0.05 mg group B, or 0.02 mg group C). We estimated the difference in uterine artery pulsatily index, endometrial thickness and histological dating and morphometric analysis of endometrium. No significant differences in Pulsatility Index values and in the number of preovulatory follicles were noted. The difference between endometrial thickness, histological dating and morphometric analysis of the endometrium were statistically different between groups B and C vs. A. Our study shows that CC has a deleterious effect on endometrium maturity and that adding ethinyl-E(2) produces a favorable endometrial response even with very low doses.     

The combined effect of bromocriptine and clomiphene citrate on normoprolactinemic anovulation; the lack of effectiveness of clomiphene citrate treatment alone

The purpose of this study is to investigate the combined effect of bromocriptine and clomiphene citrate (Cl) treatment on 35 patients with normoprolactinemic amenorrhea who failed to respond to Cl alone. Ovulation was restored by this treatment in 20 of these patients (57.1%), and the pregnancy rate was 26.7%. This treatment was effective in 11 of 15 women with polycystic ovary like syndrome (73.3%). Resting levels of prolactin, estradiol and testosterone in the effective group were significantly higher than those in the non-effective group. As a result of the treatment, the prolactin and LH levels were significantly decreased, and estradiol and progesterone levels were significantly increased in the effective group. Before the treatment, the responsiveness of LH to LHRH in the effective group was significantly higher, but the responsiveness of prolactin to TRH in this group was not significantly higher than that in the non-effective group. After the treatment, the LH-releasing response following a premarin injection in the effective group was significantly higher than that in the non-effective group. The present results indicate that the therapeutic effect of this treatment may be primarily due to the restoration and improvement of the impaired hypothalamo-pituitary system without the suppression of pituitary prolactin secretion.     

Impact of estradiol patterns in clomiphene citrate/human menopausal gonadotropin/cetrorelix protocol.

The importance of serum estradiol changes associated with gonadotropin-releasing hormone antagonists is not clear. The purpose of the present study was to analyze the impact of estradiol changes after cetrorelix injection on the outcome of intracytoplasmic sperm injection (ICSI) cycles. This was a prospective observational study. One hundred and thirteen women with male-factor infertility who were undergoing first ICSI cycles were reviewed for this study. Excluding seven cycles with incomplete data, 106 cycles were included in the analysis. The women were stimulated with clomiphene citrate and human menopausal gonadotropin (hMG). Cetrorelix acetate (2.5 mg) was given when the leading follicles reached 14 mm. After cetrorelix administration, serum estradiol rose in 48 cycles (45.3%), plateaued in 26 cycles (24.5%) and dropped in 32 cycles (30.2%). Mean age and day-3 follicle-stimulating hormone, luteinizing hormone and estradiol levels were similar among the three groups. The mean ampoules of hMG used, estradiol levels on the day of human chorionic gonadotropin injection and the clinical outcomes, including numbers of oocytes retrieved and fertilization, implantation and pregnancy rates, were similar in all three groups regardless of the trend of estradiol. In conclusion, estradiol patterns after cetrorelix injection show no correlation with clinical outcome and ovarian reserve, and falling estradiol is not associated with adverse outcome.