A randomized double-blind comparison of the effects of clomiphene citrate and the aromatase inhibitor letrozole on ovulatory function in normal women

OBJECTIVE: To evaluate the ovarian follicular dynamics of cycle modification with the aromatase inhibitor letrozole compared with clomiphene citrate in normal ovulatory women. DESIGN: Randomized double-blind controlled trial. SETTING: Tertiary care hospital. PATIENT(S): Nineteen ovulatory female volunteers, ages 18-35 years. INTERVENTION(S): Subjects were monitored in one control cycle. Subjects then received either letrozole 2.5 mg daily or clomiphene citrate 50 mg daily on days 5-9 after menses. MAIN OUTCOME MEASURE(S): Number of mature follicles, endometrial thickness and endometrial pattern at ovulation, and follicular profiles of LH, FSH, and E(2). RESULT(S): The number of mature follicles at the LH surge in natural cycles was 1.0 with an exaggerated response seen for treatment both with clomiphene and letrozole. There was no difference in the endometrial thickness at midcycle during either the natural cycles or the medicated cycles. LH surges and spontaneous ovulation were documented in all natural and medicated cycles. When measured daily, follicular profiles of LH and FSH are similar between the groups in both the natural and medicated cycles. In the medicated cycles, clomiphene results in a significant increase in E(2) levels, while E(2) levels in letrozole-stimulated cycles appeared lower than in natural cycles. CONCLUSION(S): Transient inhibition of aromatase activity in the early follicular phase with the aromatase inhibitor letrozole results in stimulation of ovarian folliculogenesis similar to that seen with clomiphene citrate with no apparent adverse effect on endometrial thickness or pattern at midcycle.     

不同年龄段不孕患者控制性超排卵中卵巢低反应的预测

目的研究不同年龄段不孕患者超排卵过程中卵巢低反应的发生情况,探讨不同年龄段患者卵巢低反应的相关因素及比较各预测指标的诊断价值。方法回顾性分析中山大学附属孙逸仙医院生殖医学中心2424个体外受精/卵细胞浆内单精子注射（IVF/ICSI）周期。按年龄分为4组,比较各组卵巢低反应的发生率及妊娠率;logistic回归分析基础FSH、基础LH、基础E2、窦卵泡数（AFC）、卵巢容积和BMI等与卵巢低反应的相关性,并根据回归结果计算联合指标的ROC曲线。结果 18～30岁组不孕患者卵巢低反应率为9.0%（77/852）,基础FSH与AFC联合预测卵巢低反应的ROC曲线下面积为0.726;31～35岁组卵巢低反应率为19.7%（172/871）,基础FSH、基础LH、AFC联合预测卵巢低反应的ROC曲线下面积为0.789;36～40岁组卵巢低反应率34.9%（190/545）,基础FSH、卵巢体积、AFC和年龄联合预测卵巢低反应的ROC曲线下面积为0.831;≥41岁组卵巢低反应率为69.2%（108/156）,AFC预测卵巢低反应的ROC曲线下面积为0.809。结论随着年龄增大,卵巢低反应发生率增加、妊娠率下降;不同年龄段预测卵巢低反应的指标不同,综合多指标的预测价值较单一指标预测价值高,建议综合多个有效指标评估卵巢的反应性。     

Aromatase inhibition improves ovarian response to follicle-stimulating hormone in poor responders

OBJECTIVE: To examine the use of the aromatase inhibitor letrozole with FSH for ovarian stimulation in poor responders undergoing ovarian superovulation and IUI. DESIGN: Observational cohort study as a prospective clinical trial in patients with unexplained infertility and a low response to ovarian stimulation with FSH. SETTING: Two tertiary referral infertility clinics associated with the Reproductive Sciences Division, University of Toronto. PATIENT(s): Twelve patients with unexplained infertility undergoing IUI who received FSH alone in 25 prior cycles with poor response (less than three dominant follicles). INTERVENTION(s): Patients were offered letrozole, 2.5 mg/day from day 3-7 of the menstrual cycle with FSH (50-225 IU/day) starting on day 5-7. hCG (10,000 IU) was given when two leading follicles were >/=2 cm followed by IUI. MAIN OUTCOME MEASURE(s): Number of mature follicles (>1.8 cm), FSH dose, endometrial thickness, and pregnancy rate. RESULT(s): Improved response to FSH stimulation with letrozole co-treatment was evidenced by the significantly lower FSH dose associated with significantly higher number of mature follicles. During letrozole plus FSH stimulation cycles, clinical pregnancy was achieved in three cycles (21%). CONCLUSION(s): In this preliminary report, we demonstrate a potential benefit of aromatase inhibition for improving ovarian response to FSH in poor responders.     

A randomized comparison of ovulation induction and hormone profile between the aromatase inhibitor anastrozole and clomiphene citrate in women with infertility

Background. In the present study we evaluated and compared the effects of ovulation and hormonal dynamics induced by anastrozole and clomiphene citrate in women with infertility.

Materials and methods. Thirty-three infertile patients, aged 25–41 years, were enrolled. Patients received either anastrozole 1 mg daily (AI group) or clomiphene citrate 100 mg daily (CC group) from cycle day 3 to day 7. Number of mature follicles (≥18 mm), endometrial thickness, pregnancy rate and serial hormone profiles (follicle-stimulating hormone (FSH), luteinizing hormone (LH), estradiol (E₂), testosterone and progesterone) were measured on cycle day 3, day 8, day 10, the day of intrauterine insemination (IUI), day 7 after IUI and day 14 after IUI.

Results. Baseline parameters were similar in the two groups, including age, body mass index, infertility duration and day-3 serum hormones except FSH. The mean FSH value on day 3 was significantly different (4.3 mIU/ml in the AI group vs. 6.3 mIU/ml in the CC group; p < 0.05). The women receiving anastrozole had fewer ovulatory follicles (1.2 in the AI group vs. 1.8 in the CC group; p < 0.05) and a thicker endometrium (10.6 mm in the AI group vs. 7.8 mm in the CC group; p < 0.05). The levels of progesterone and testosterone were similar during ovulation stimulation cycles in both groups. On the other hand, the AI group had a significantly higher LH level but a significantly lower E₂ level in the stimulation cycle.

Conclusion. Anastrozole has a high pregnancy rate, although it induces fewer ovulatory follicles compared with clomiphene citrate. The two drugs gave different responses of FSH, LH and E₂ during stimulation cycles.     

A phase I study of the pharmacokinetics, pharmacodynamics, and safety of single- and multiple-dose anastrozole in healthy, premenopausal female volunteers

OBJECTIVE: To evaluate the pharmacokinetic, pharmacodynamic, and safety profiles of the aromatase inhibitor anastrozole in healthy, premenopausal women. DESIGN: Phase I, single-center study. SETTING: Infertility clinic. PATIENT(S): Twenty-six women with regular ovulatory cycles: 20 received either a single dose of 5 mg, 10 mg, 15 mg, or 20 mg anastrozole, or remained untreated; 6 received five daily doses of 10 mg or 15 mg anastrozole. INTERVENTION(S): Anastrozole was administered on cycle day 2 for the single-dose groups and on days 2-6 for the multiple-dose groups. Ultrasound follicular development and endometrial biopsies were performed. Safety was determined from adverse event reports and laboratory parameters. MAIN OUTCOME MEASURE(S): Pharmacokinetics, pharmacodynamics, and safety. RESULT(S): The pharmacokinetics of anastrozole were linear, predictable, and consistent with previously published data in healthy volunteers. In the single-dose groups, E2 levels reached their nadir 3-6 hours after administration, decreasing by an average of 39% from baseline. Follicle-stimulating hormone levels rose by 13%, 52%, 49%, and 75% in the 5-mg, 10-mg, 15-mg, and 20-mg groups, respectively, at approximately 24 hours after dosing. Most subjects recruited just one mature follicle, with no apparent effect on endometrial maturation. No safety concerns were noted. CONCLUSION(S): Anastrozole was well tolerated and suppressed E2 levels, with a resultant increase in FSH.     

Treatment of infertile women with unilateral tubal occlusion by intrauterine insemination and ovarian stimulation

ObjectiveThe aim of this study was to evaluate the value of intrauterine insemination (IUI) combined with ovarian stimulation in women with unilateral tubal occlusion detected on hysterosalpingography (HSG).Materials and MethodsA total of 703 patients undergoing IUI and controlled ovarian hyperstimulation were enrolled in this study. The study group consisted of 133 patients treated for unilateral tubal occlusion diagnosed by HSG during 2005–2011. The control group consisted of 570 patients with unexplained infertility treated during the same period. In all cases of the retrospective study, menstrual cycles were regular, basal serum follicle-stimulating hormone levels and sperm parameters were normal.ResultsThere were no significant differences in pregnancy rate per cycle between the study (17.3%) and control groups (18.9%). The pregnancy rate was higher in patients with proximal tubal occlusion (21.7%) compared with mid-distal tubal occlusion (12.5%) or unexplained infertility (18.9%), but the difference was not statistically significant.ConclusionsInfertile patients with only unilateral proximal tubal occlusion detected on HSG can be treated initially by IUI combined with ovarian stimulation. The cycle outcomes in patients with proximal tubal occlusion are similar to patients with unexplained infertility. However, the stimulated IUI might not be a good choice for patients with unilateral mid-distal tubal occlusion because of a lower success rate, although further evidence is needed.     

Clinical background affecting pregnancy outcome following local endometrial injury in infertile patients with repeated implantation failure

Local endometrial injury (LEI) has been performed as a promising medical intervention to improve the pregnancy outcome in infertile women suffering from repeated implantation failure (RIF) in in vitro fertilization-embryo transfer cycles. The effect of LEI, however, remains controversial. The aim of this retrospective study was to identify the subgroups of patients with RIF who benefit from LEI. We compared the clinical parameters between the patients who had had a clinical pregnancy in the subsequent embryo transfer cycle following the LEI cycle (LEI-CP group, n?=?94) and those who had resulted in negative pregnancy test (LEI-NP group, n?=?114). The female age, basal follicle stimulating hormone concentration, number of past oocyte pickup cycles, and embryos/blastocysts transferred in the past three RIF cycles were significantly (p?p?=?0.0059) higher in the LEI-CP group than in the LEI-NP group. These findings suggest that LEI is most effective to improve the pregnancy outcome in patients undergoing RIF with uncompromised ovarian reserve, particularly in those with polycystic ovarian syndrome.     

不同促排卵方法在卵巢储备功能下降患者中的应用

目的:探讨卵巢储备功能下降患者的促排卵优选方案。方法:GnRH-a/hMG/rFSH(Gn)长方案促排卵(A组)共39个周期,GnRH-a/hMG/rFSH(Gn)短方案促排卵(B组)46个周期,GnRH-A/hMG/rFSH(Gn)促排卵(C组)共35个周期,比较3组临床用药和临床结局情况。结果:A组Gn所用天数(12.4±1.51d)显著高于B组(9.5±1.7d)、C组(10.7±3.2),P<0.05,且Gn(75IU/支)所用支数(41.5±8.6支)也明显多于B组(34.7±9.7支)和C组(33.4±16.2支)(P<0.05)。B组Gn所用天数要少于C组(P<0.05),Gn所用总量与C组间无统计学差异(P>0.05)。hCG注射日的血清LH水平A组(1.20±1.02IU/L)显著低于B组(3.17±1.58IU/L)和C组(2.15±1.8IU/L)(P<0.05),B组与C组之间无统计学差异(P>0.05)。A组与C组注射hCG日的血清E2值(7958±4586pmol/L,6022±7852pmol/L)均低于B组(10145±5503pmol/L)(P<0.05)。3组种植率、临床妊娠率均无显著性差异。3组间hCG注射日内膜厚度、受精率、卵裂率均无统计学差异(P>0.05)。结论:短方案更适合于卵巢功能减退患者的促排卵治疗,长方案与GnRH-A方案促排卵也是可行方法。     

Luteolysis induced by a gonadotropin-releasing hormone agonist is the key to prevention of ovarian hyperstimulation syndrome

OBJECTIVE: To review the available knowledge on the use of GnRH agonist for ovulation triggering as a means to prevent ovarian hyperstimulation syndrome (OHSS). DESIGN(S): Review of pertinent English language studies published over the past 15 years. RESULT(S): The available literature suggests that while GnRH agonist effectively induces final oocyte maturation and ovulation, it also completely and reliably prevents clinically significant OHSS. The mechanism of action in the context of OHSS prevention involves complete, quick, and irreversible luteolysis CONCLUSION(S): Controlled ovarian stimulation protocols based on GnRH antagonist to prevent premature LH rise and GnRH agonist for ovulation triggering provide a safe and OHSS-free clinical environment. Adequate luteal support compensates for luteolysis and assures good clinical outcome. The fertility community is urged to adopt these protocols. This will make OHSS a disease of the past.     

Controlled ovarian hyperstimulation interventions in infertile women aged 40 years or older undergoing in vitro fertilization

Background

The success of in vitro fertilization (IVF) treatment depends on adequate follicle recruitment following controlled ovarian hyperstimulation (COH). Women aged 40 years or older have a reduced ovarian reserve and various treatment protocols have been proposed that aim to increase their ovarian response.

Objectives

To compare the effectiveness of different COH treatment interventions in women undergoing IVF aged 40 years or older.

Search strategy

MEDLINE, the Cochrane Library, and the Chinese Biomedical database were searched for randomized controlled trials (RCTs).

Selection criteria

Only RCTs comparing one type of COH intervention with another in women undergoing IVF aged 40 years or older were included.

Data collection and analysis

Two authors independently searched the abstracts, identified relevant papers, assessed inclusion and trial quality, and extracted the relevant data.

Main results

Four trials involving 4 different comparison groups were included in the review and enrolled a total of 611 randomized subjects.

Conclusion

There was insufficient evidence to support the routine use of any particular COH intervention to manage infertile women aged 40 years or older undergoing IVF. More robust data from good quality RCTs with relevant outcomes are needed.     

Hormonal treatments and epithelial ovarian cancer risk

Exogenous sex hormones are widely used by women either for pregnancy prevention, as part of infertility treatment, or for treatment of menopausal symptoms. The role of these hormones in the development of ovarian cancer has been vastly explored. The protective effect of combined oral contraceptive pill is confirmed in multiple studies, but it is not clear whether this protection also covers women with a genetic predisposition to ovarian cancer. There is no conclusive evidence of infertility treatments increasing ovarian cancer risk, but infertility as such is a risk factor. Currently available data suggest that long-term users of hormone replacement therapy may have a slightly increased risk for ovarian cancer compared to women who have never used estrogen. The risk might particularly involve the endometrioid type of ovarian cancer. Most data on ovarian cancer and estrogen comes from epidemiological studies, since the normally high concentrations of estrogens in ovarian tissue and follicular fluid make direct biologic studies on the effects of exogenous estrogens on the ovarian cell difficult. This review discusses the risk of ovarian cancer associated with the use of sex steroid hormones, with special emphasis on the possible risk associated with estrogens.     

Predictive value of repeated measurements of luteal progesterone and estradiol levels in patients with intrauterine insemination and controlled ovarian stimulation

Objective: The objective of this study is to assess if the difference of repeated measurements of estradiol and progesterone during luteal phase predict the outcome of intrauterine insemination.

Design: Prospective study.

Setting: Reproductive clinic.

Patients: 126 patients with infertility.

Intervention(s): Patients underwent controlled ovarian stimulation with recombinant FSH (50–150?IU/d). The day of IUI patients were given p.o natural micronized progesterone in a dose of 100?mg/tds.

Results: The area under the receiver characteristic operating curve (ROC curve) in predicting clinical pregnancy for % change of estradiol level on days 6 and 10 was 0.892 with 95% CI: 0.82–0.94. A cutoff value of change >??29.5% had a sensitivity of 85.7 with a specificity of 90.2. The corresponding ROC curve for % change of progesterone level was 0.839 with 95% CI: 0.76–0.90. A cutoff value of change >??33% had a sensitivity of 85 with a specificity of 75.

Conclusions: The % change of estradiol and progesterone between days 6 and 10 has a predictive ability of pregnancy after IUI with COS of 89.2% and 83.4%, respectively. The addition of % of progesterone to % change of estradiol does not improve the predictive ability of % estradiol and should not be used.     

Direct intraperitoneal insemination and controlled ovarian hyperstimulation in subfertile couples

Method We performed direct intraperitoneal insemination in combination with superovulation and washed husband's spermatozoa as the treatment of infertility caused by oligospermia, cervical subfertility, or ovulatory dys-function or idiopathic infertility in 162 couples during 360 cycles.Results The pregnancy rate per couple was 21.9% in the cervical-factor group, 20.9% in the idiopathic group, 4.9% in the oligospermia group, and 15.5% in the ovulatory dysfunction group.Conclusion The pregnancy rate was 33.3% for all couples and 15.0% for all cycles.