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。     

Effect of clomiphene citrate on endometrium thickness and echogenic patterns.

OBJECTIVE: To study the effect of clomiphene citrate (CC) on the thickness and echogenic pattern of the endometrium using vaginal sonography. METHOD: In this experimental prospective study, CC was given to 31 women with unexplained infertility. Thickness and echo patterns of the endometrium, as well as estradiol (E2) and progesterone (P) levels, were compared in women taking CC and in control patients during both the late proliferative and midsecretory phases of the menstrual cycle. RESULTS: Endometrial thickness was significantly thinner in women taking CC (P<0.03) than in controls during the late proliferative phase but there was no significant difference during the midsecretory phase. The endometrial echogenic patterns of women taking CC who had conceived revealed endometrial thicknesses of grade III and grade IV on midsecretory days, but these findings were not significantly different from those of women who had not conceived (P=0.3). Serum E2 level was higher in women taking CC than in the controls on both late proliferative and midsecretory days (P<0.05). CONCLUSION: CC affects endometrium thickness on late proliferative days but not on midsecretory days, and does not alter the echogenic pattern of the endometrium.     

The effects of clomiphene citrate on normally ovulatory women

Objective: To investigate the efficacy of clomiphene citrate (CC) on normally ovulatory women who complained of infertility.

Design: A randomized study.

Setting: University Hospital.

Patient(s): Thirty-three normally ovulatory women with unexplained infertility.

Intervention(s): Eighteen women received CC at a 50-mg dosage. Fifteen women received no ovulation-induction drugs.

Main Outcome Measures: The pregnancy rate (PR) per patient, the PR per cycle, and the cumulative pregnancy rate.

Result(s): Seven patients in the CC group stopped taking CC, and observations were terminated because of antiestrogenic effects. The pregnancy rate (PR) per patient and the PR per cycle were significantly decreased (P < 0.005) in the CC group (4 of 18 [22.2%] and 4 of 66 [6.1%], respectively) than in the spontaneous group (11 of 15 [73.3%] and 11 of 52 [21.2%], respectively). Kaplan-Meier tests showed that the cumulative pregnancy rate in the CC group was significantly lower than in the spontaneous group (P <0.05). Five of seven patients who had stopped taking CC became pregnant in spontaneous cycles.

Conclusion(s): Administration of CC to normally ovulatory women is not efficacious in terms of increasing the pregnancy rate.     

克罗米芬兴奋试验预测卵巢储备功能的价值

目的探讨克罗米芬兴奋试验（CCT）在不孕妇女中预测卵巢储备功能的作用。方法对2001年1月至2005年2月就诊于广东省妇幼保健院的666例不孕症患者作为研究对象，分为A组（≥35岁）461例为高龄组，B组（〈35岁）205例为低龄组，另取156例年龄〈35岁、非女方不孕原因者作为对照组，对三组受试者进行CCT。结果CCT异常发生率A组、B组及对照组分别为27．76％、34．14％、2．56％，A组及B组与对照组比较差异均有非常显著性意义（P〈0．01）。基础卵泡刺激素（FSH）〈10IU／L、雌二醇（E2）〈180pmot／L的不孕患者CCT异常发生率分剐为17．46％、24．19％，均明显低于FSH≥10IU／L、E2≥180pmol／L患者的64．19％及39．4％（P〈0．01）。结论CCT预测卵巢储备功能较基础FSH更敏感，CCT可作为常规了解卵巢储备功能的一项检测方法。     

克罗米芬联合促卵泡素治疗多囊卵巢综合征的疗效观察

目的:比较单用克罗米芬(CC)及其联合不同促卵泡素(FSH)治疗多囊卵巢综合征(PCOS)患者的效果,以指导PCOS患者选择合适的促排卵方案.方法:选取2009年1月至2012年7月就诊于我院生殖门诊的81例PCOS患者(共92周期),患者均以CC促排卵,根据月经第8天的卵泡生长情况,决定是否联合应用基因重组促卵泡素(rFSH)或尿促卵泡素(uFSH).按促排卵方案不同将患者分为3组:CC+ HCG组(A组,26例,32周期);CC+rFSH+HMG+HCG组(B组,23例,26周期);CC+uFSH+HMG+HCG组(C组,32例,34周期).患者排卵后均用黄体酮胶丸或地屈孕酮黄体支持12 ～ 14天.比较3组患者促排卵治疗的效果.结果:A组中2例患者发生黄素化综合征(LUFS);B组中4例发生轻度卵巢过度刺激综合征(OHSS);C组中1例发生重度OHSS,1例LUFS.3组患者的HCG日最大卵泡直径、内膜厚度、排卵率及妊娠率均无显著差异(P＞0.05).A组D8优势卵泡直径大于B、C组(P＜0.05);至HCG日平均时间少于B、C组(P＜0.05);B组直径≥1.5cm卵泡数和排卵数均显著高于A、C组(P＜0.05).B组与C组的至HCG注射日时间和FSH用量均无显著差异(P＞0.05).结论:CC促排周期D8优势卵泡直径大小对决定联合FSH治疗PCOS患者有一定的参考意义.单用CC促排卵可能抵抗周期,联合uFSH是经济有效的促排卵方案.     

Clomiphene citrate affects the receptivity of the uterine endometrium

PurposeTo investigate whether clomiphene citrate (CC) affects uterine receptivity or not, we evaluated pregnancy rates (PR) during the hormone replacement cycle (HRC) according to the period between the last day of CC administration and the day of embryo transfer (ET).MethodsFrom March 2008 through March 2010, a total of 378 treatment cycles among 378 patients who received CC and had to avoid fresh ET due to a thin uterine endometrium were recruited. All patients underwent thawed ET using HRC. PRs were evaluated according to the period between the last CC treatment and the day of ET.ResultsPR for the groups in which the period between the last CC treatment and the day of ET increased to more than 91 days were significantly higher than that for group in which the period was less than 90 days (p < 0.05).ConclusionsA lower PR was shown by the patients who underwent thawed ET in the HRC within 90 days after their last CC treatment, which shows that CC affects the receptivity of the uterine endometrium.     

Extension of the clomiphene citrate stair-step protocol to gonadotropin treatment in women with clomiphene resistant polycystic ovarian syndrome

Our objective was to evaluate the safety and efficacy of direct initiation of gonadotropin ovarian stimulation without prior withdrawal bleeding in anovulatory clomiphene citrate (CC) resistant polycystic ovarian syndrome (PCOS) patients. Eighteen PCOS patients underwent ovulation induction with CC using a stair-step regimen. Patients who failed to respond to the maximal dose of CC initiated gonadotropin stimulation without inducing withdrawal bleeding, using the chronic low dose regimen. The primary outcome measure was the time to ovulation from the beginning of CC treatment until the day of ovulatory trigger. This was compared with the time to ovulation calculated according to the traditional approach, which includes inducing progesterone withdrawal bleeding between each CC dose increment and before gonadotropin therapy. The time to ovulation in the study group was 67.0?±?6.8 days. The estimated time to ovulation according to the traditional approach was approximately 110 days. The clinical pregnancy rate was 44% (8/18), and all pregnancies were singletons. One patient miscarried; hence the live birth rate was 38.9% (7/18). Direct initiation of gonadotropin therapy without prior induction of withdrawal bleeding in clomiphene resistant PCOS patients results in considerable reduction of the time to ovulation and is both safe and efficacious.     

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.     

Time of initiation of clomiphene citrate and pregnancy rate in polycystic ovarian syndrome.

OBJECTIVE: To investigate whether the timing of clomiphene citrate (CC) administration affects hormonal levels, follicular growth, endometrial thickness, and ovulation and pregnancy rates in women with polycystic ovarian syndrome (PCOS). METHODS: Of the 78 infertile women with PCOS who participated in this prospective, double-blind, randomized clinical trial, 37 collectively underwent 71 cycles of CC (100 mg/day) on days 1 through 5 of the menstrual cycle (group 1) and 41 collectively underwent 73 cycles of CC at the same concentration on days 5 through 9 (group 2). Hormonal levels, follicular growth, endometrial thickness, and ovulation and pregnancy rates were compared. RESULTS: The mean number of follicles and the maximum follicular size were greater in group 2. However, ovulation rates were 72.8% in group 1 and 70.8% in group 2 (P=.78), and pregnancy rates were 40.5% in group 1 and 19.5% in group 2 (P=.04). CONCLUSION: Treatment with CC is associated with higher rates of pregnancy if started early (days 1-5) in the menstrual cycle.     

Transfer of cryopreserved - thawed embryos in hCG induced natural or clomiphene citrate cycles yields similar live birth rates in normo-ovulatory women

Introduction  

The purpose of this retrospective analysis is to compare the efficiency of hCG-induced natural and Clomiphene citrate (CC) cycles in normovulatory patients undergoing frozen embryo transfer (FET).     

The effect of clomiphene citrate on osteoporosis in ovariectomized rats

OBJECTIVE: The aim of this study was to investigate whether clomiphene citrate (CC) administration could be a new therapeutic agent in case of contraindication of estrogen therapy for hormone-dependent osteoporosis and to show the changes in bone structure by histomorphometric analysis in ovariectomized rats administered CC. STUDY DESIGN: This study was carried out in the Experimental Surgery Laboratory of the Brain Research Centre of the Medical Faculty of Ege University. Four-month-old Sprague-Dawley rats were used for the experiment. The study was carried out on six groups of animals each consisted of eight rats. Four groups of rats were ovariectomized and 2 groups of rats were used as control group. For 6 weeks every day, rats were injected physiological saline solution (1 ml/kg), clomiphene citrate (1 or 10 mg/1 ml/kg, Organon), 17beta-estradiol (50 microg/1 ml/kg, within susame oil, Sigma) or susame oil (1 ml/kg, Sigma). Drug administrations were carried out according to the weekly weight measurements. Group 1(PSS), n = 8, non-ovariectomized, were injected with physiological saline solution. Group 2(CC-1), n = 7, non-ovariectomized, were injected with CC (1 mg/1 ml/kg). Group 3(OVX + CC-1), n = 7, ovariectomized, were injected with CC (1 mg/1 ml/kg). Group 4(OVX + CC-10), n = 6, ovariectomized, were injected with CC (10 mg/1 ml/kg). Group 5(OVX + E), n = 8, ovariectomized, were injected with 17beta-estradiol (50 microg/1 ml/kg). Group 6(OVX), n = 8, ovariectomized, were injected with susame oil (1 ml/kg) Bone-specific serum alkaline phosphatase (ALP) levels were measured and statistical analyses were made by Kruskal Wallis test. Left femur bone histomorphometric studies were done. The uteri were dissected out to measure their weight and ANOVA was used to show the intergroup differences. RESULTS: The level of ALP in group 3 was significantly higher than the other five groups. Bone histomorphometric examination showed that total bone volume in group 3, 4, and 5 was higher than group 6, and group 4 had the highest level of bone volume compared to the rest of the groups. Uterus weights in group 1 were significantly higher than group 3 and 6 (P = 0.02, P = 0.01) and uterus weights in group 5 were significantly higher than group 3 and 4 (P = 0.00, P = 0.01) CONCLUSIONS: In ovariectomized rats, treatment with CC is seen as effective as estrogen treatment in preventing osteoporosis, without causing uterin hyperstimulation. Nevertheless, further investigations on more rats are needed to assess whether it is an alternative treatment method to estrogen.     

Effects of clomiphene citrate on the endometrium of regularly cycling women

OBJECTIVE: To study the effects of clomiphene citrate (CC) on the endometrium of regularly cycling women. DESIGN: Prospective, controlled study. SETTING: Department of Obstetrics and Gynaecology, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand. PATIENT(S): Thirty healthy, regularly cycling, female volunteers. INTERVENTION(S): All volunteers were studied for two consecutive cycles, one control cycle and one CC-treated cycle. Clomiphene citrate (100 mg/d) was given on days 3-7 of the CC-treated cycles. Ultrasonography was performed daily to assess ovulation. Ultrasonography and endometrial biopsy were performed, and blood samples were obtained for determination of E2 and progesterone levels 7 days after ovulation in both the control and CC-treated cycles. MAIN OUTCOME MEASURE(S): Histologic dating, morphometric analysis, and ultrasonographic appearance and thickness of the endometrium. RESULT(S): Histologic dating and ultrasonographic appearance and thickness of the endometrium were similar in the control and CC-treated cycles, but morphometric parameters were different. The number of glands per square millimeter and the mean diameter of the glands were lower in the CC-treated cycles than in the control cycles, but the number of vacuolated cells per 1,000 glandular cells was higher. CONCLUSION(S): Clomiphene citrate has effects on the endometrium of regularly cycling women, as demonstrated by a reduction in glandular density and an increase in the number of vacuolated cells.     

Differential expression of functionality markers in mid-secretory endometrium of infertile women under treatment with ovulation-inducing agents

Objectives

To analyze the expression of protein markers related to cell proliferation and death, as well as oestrogen and progesterone receptors in the endometrium of infertile women with hypothalamic–pituitary dysfunction treated with clomiphene citrate (CC) or recombinant follicle-stimulating hormone (rFSH), and compare them with ovulatory women.

Study design

The study included 12 control ovulatory women and 29 anovulatory women, 19 of whom underwent ovulation induction with CC (n = 12) or rFSH (n = 5). Endometrial biopsies were obtained by Pipelle during the mid-secretory phase. Samples were stained with haematoxylin and eosin. Immunohistochemistry of proteins related to cell proliferation and cell death, as well as steroid receptors, was undertaken, and apoptosis was determined using TUNEL analysis.

Results

Immunohistochemical analysis of Ki67 expression showed significantly higher expression in the glandular epithelium of ovulatory women compared with the other groups. Glandular oestrogen receptor α expression was significantly lower in rFSH-treated women compared with ovulatory women. The number of apoptotic cells, Bax expression and progesterone receptor expression were similar in all groups. In contrast, Bcl-2 expression was significantly lower in the glandular epithelium of rFSH-treated women.

Conclusions

In infertile women with hypothalamic–pituitary dysfunction, treatment with ovulation-inducing agents modifies the expression of proteins involved in cell proliferation and death, as well as the expression of steroid hormone receptors in the endometrium. These differences may help to explain, at the molecular level, the functionality of the endometrium during the implantation window, and may help to optimize pregnancy rates obtained with these treatments.     

Embryo toxicity of clomiphene citrate on mouse embryos fertilized in vitro and in vivo

The effect of the ovulatory agent clomiphene citrate on fertilization and early embryogenesis was investigated with the use of in vitro fertilized mouse oocytes. Alterations in early embryogenesis with clomiphene citrate exposure were further studied with the use of embryos obtained from mouse oocytes fertilized in vivo. In the nontreated group, the fertilization rate was 81%, and 61% of the oocytes reached the blastocyst stage by 96 hours. Both fertilization and blastocyst formation declined in a dose-dependent fashion when clomiphene citrate was added to the culture media in concentrations greater than or equal to 10 micrograms/ml (p less than 0.001). The rate of progressive embryo cleavage was also slower at 48 and 72 hours after drug exposure. Mouse embryos fertilized in vivo demonstrated similar findings, with decreased blastocyst formation and increased degeneration rates, again at clomiphene citrate concentrations greater than or equal to 10 micrograms/ml (p less than 0.01). Exposure to the drug beyond 24 hours had no additional effect. It appears that clomiphene citrate-exposed embryos may undergo subtle changes that later manifest themselves in the form of decreased embryo growth rates and increased embryo degeneration rates.     

Endometrial effects of letrozole and clomiphene citrate in women with polycystic ovary syndrome using spiral artery Doppler

Objectives  To compare the effects of letrozole and clomiphene citrate (CC) on endometrial response in PCOS using subendometrial spiral artery Doppler. Methods  Fifty consecutive patients of anovulatory PCOS were recruited. Twenty-five patients (58 cycles) received 2.5–5 mg of letrozole; 25 patients (56 cycles) received 50–100 mg of CC (both orally on days 5–9 of menses). Main outcome measures: number of dominant follicles, endometrial thickness (ET), spiral artery resistance index (RI) and pulsatility index (PI) and pregnancy rate. Results  The mean number of dominant follicles in letrozole group and CC groups was 1.63 ± 1.02 and 1.62 ± 0.96, respectively (P > 0.05). The mean mid cycle ET was 6.9 ± 0.74 mm in letrozole group and 5.9 ± 0.53 mm in CC group (P < 0.05). In letrozole and CC groups, the mean RI of spiral artery were 0.63 ± 0.05 and 0.79 ± 0.09, respectively, and the mean PI of spiral artery were 1.19 ± 0.06 and 1.55 ± 0.13, respectively. Both RI and PI in the letrozole group showed significant lower impedance compared to CC group (P < 0.05). Pregnancy rate per cycle was 19% (11/58) in the letrozole group and 12.5% (7/56) in the CC group (P > 0.05). Conclusion  The effect of letrozole showed a significantly better endometrial response compared to CC.     

Endometrial biopsy during induction of ovulation with clomiphene citrate in polycystic ovary syndrome

Background.?The dichotomy between ovulation rates and pregnancy rates for women with polycystic ovary syndrome (PCOS) treated with clomiphene citrate (CC) prompted the present study to determine the effect of CC on endometrial maturity.

Methods.?Retrospective case–control study of anovulatory women with PCOS (n = 119) on their third ovulatory cycle of CC and controls, 238 healthy regularly ovulating women whose partners had abnormal sperm, all of whom had an endometrial biopsy in the late luteal phase.

Results.?Endometrial histology classified according to the classical Noyes criteria revealed out-of-phase endometrium in 19/119 (16%) of the CC group compared with 7/238 (3%) in controls (p < 0.0001). Duration of the luteal phase was not influenced by histological age of the endometrium. Endometrial biopsy performed during 138 conception cycles extracted from the database did not increase the miscarriage rate significantly (23.9%).

Conclusions.?CC treatment significantly increases the prevalence of out-of-phase endometrium and this could explain, in part, the large difference between ovulation and pregnancy rates. There was no correlation between the results of the endometrial biopsy and the duration of the luteal phase. Performing an endometrial biopsy during a conception cycle does not seem to have a significant negative effect on the outcome of pregnancy.     

Predictive usefulness of cycle day 10 follicle-stimulating hormone level in a clomiphene citrate challenge test for in vitro fertilization outcome in women younger than 40 years of age

OBJECTIVE: To determine the usefulness of the day 10 FSH level of a clomiphene citrate challenge test in predicting IVF outcome in women younger than 40 years of age. DESIGN: Retrospective chart review. SETTING: Academic fertility center. PATIENT(S): Three hundred fifty-three women younger than 40 years of age undergoing 483 IVF cycles. MAIN OUTCOME MEASURE(S): Delivery rates. RESULT(S): An inverse relationship was observed between the likelihood of successful pregnancy and both cycle day 3 and cycle day 10 FSH levels. In women with a normal day 3 FSH level, elevated day 10 FSH levels predicted similarly poor IVF outcomes as for women with an abnormal day 3 FSH level. There was no specific threshold FSH level beyond which pregnancies failed to occur. Successful pregnancies were achieved with aggressive stimulation even in women with FSH levels greater than 20 mIU/mL. CONCLUSION(S): The clomiphene citrate challenge test (CCCT) correlates with IVF outcomes in women younger than 40 years of age. Stimulated day 10 FSH levels are strongly predictive of decreased IVF success even when day 3 FSH levels are normal. Results of the CCCT are useful for patient counseling before the IVF cycle and for choosing the optimal gonadotropin regimen.     

Evaluating the equivalence of clomiphene citrate with and without metformin in ovulation induction in PCOS patients

Objective  To evaluate the benefit of Metfomin added to Clomiphene Citrate in a primary ovulation induction protocol in PCOS patients Design  Prospective randomised controlled study Setting  Tygerberg Academic Hospital, Stellenbosch University and the Institute of Reproductive Medicine at Vincent Pallotti Hospital, Cape Town Patients  107 patients presenting with PCOS Study  Group A was pre-treated with metformin 850 mg twice a day for at least 6 weeks before clomiphene was added and the metformin was used throughout the study period. Group B received clomiphene without pre-treatment with metformin. In both groups clomiphene was given at a starting dose of 50 mg day 4–8 and increase with increments of 50 mg to a maximum of 150 mg if no response was achieved. Results  The ovulation rate achieved in women in the M+C/C arm was 34/52 (65.4%) compared to 36/55 (65.5%) in the C/C arm. The treatment effect ((M+C/C) – C/C) is 0% with 95% confidence interval of −18.1% to 18%. The per protocol ovulation results were 34/42 (81%) in the M+C/C arm compared to 36/48 (75%) in the C/C arm. The ovulation rate difference was 6% with 95% confidence interval −11% to 22%. In a comparison of successful ovulating versus non-ovulating women from the trial the following were significant baseline determinants: lower median weight in the ovulating group (77 kg versus 86 kg, p = .021), lower median bmi (29.0 versus 32.9, p = .009), lower median DHEAS at baseline (4.6 compared to 7.0, p = .049), lower median 17OH-progesterone (2.2 versus 4.6, p = .027) and higher baseline median SHBG ( 37.8 compared to 28.5, p = .036). Conclusion  Although identical ovulation rates were observed in both arms equivalence could not be concluded with respect to the specified criteria. Capsule   Clomiphene with Metformin achieved the same ovulation rate (65%) compared to Clomiphene alone. However the 2-sided 95% confidence interval for ovulation rate difference was −18.1% to 18%.