Low-dosage clomiphene reduces premature ovulation rates and increases transfer rates in natural-cycle IVF

Natural-cycle IVF has been suggested as an alternative IVF treatment. However, efficacy is limited due to high premature ovulation rates, resulting in low transfer rates. This study investigates whether low dosages of clomiphene citrate reduce premature ovulation rate and increase transfer rate. Of 112 women included (aged 35.2 ± 4.5 years) 108 underwent one natural-cycle IVF cycle with human chorionic gonadotrophin (HCG) to induce ovulation and 103 underwent one natural-cycle IVF cycle with 25 mg/day clomiphene from about day 7 until HCG administration. Before retrieval, 1.2 monitoring consultations per cycle were required. Clomiphene reduced premature ovulation rate, from 27.8% without to 6.8% with clomiphene (P < 0.001) and increased transfer rate from 39.8% to 54.4% (P = 0.039). Clinical pregnancy rates without and with clomiphene were 27.9% versus 25.0% per transfer and 11.1% versus 13.6% per initiated cycle. Use of clomiphene resulted in mild hot flushes and headache in 5% of patients. Nausea and persisting ovarian cyst formation was not observed. In conclusion, clomiphene citrate led to very few side effects, required 1.2 monitoring consultations, significantly reduced premature ovulation rate and significantly increased transfer rate per initiated cycle, an effect which was not age dependent.     

Metformin therapy in polycystic ovary syndrome

Polycystic ovarian syndrom (PCOS) affects 5% to 10% of women of reproductive age, and is the most common reason of anovulation in infertile women. It is multi-symptom disease. A drug which is used to induce ovulation in women with PCOS is clomiphene citrate. After clomiphene treatment, ovulation is achieved in 56%-73% of women. The rest of them has different level of opportunity to therapy. Clomiphene does not have influence on elementary factor in PCOS which seems to be opportunity to insulin. The drug which can have positive effect is metformin, derivative from biguanid. Its influence on percent of ovulation, pregnancy and live births was evaluated based on randomized trials. Many trials have reserched this so far, but their results are divergent. In this article, we are aiming to systemize results of randomized trials concerning the role of metformin in PCOS therapy.     

Effects of clomiphene citrate on cervical mucus: analysis of some influencing factors

A multicenter study was performed to investigate the effects of a standard dose of clomiphene citrate (100 mg/day from day 5 of the cycle for five days) on the quality of cervical mucus. A total of 82 cervical mucus samples from 60 infertile patients (15 with secondary amenorrhea, 16 with delayed ovulation, 15 with anovulatory cycles, 14 with oligomenorrhea) was examined on the day of maximum follicular diameter. As a control we studied 54 cervical mucus samples from 47 patients with documented tubal sterility or infertile partners, who had spontaneous cycles with normal rhythm. Cervical mucus was unfavorable in 59% of the treatment cycles compared with 11% of the control cycles. Clomiphene citrate's antiestrogenic effect on cervical mucus was found to be related to the length of time between the last drug administration and the day of maximum follicular diameter (delta days), since cervical mucus was favorable in 64% of the cycles with a delta days more than 6 and in only 16% of the cycles with a delta days of 6 or less. Clomiphene citrate thus seems able to decrease cervical mucus quality. This could be one of the causes of the discrepancy between the rates of ovulation and pregnancy reported in patients treated with this drug.     

Surgical Management of Polycystic Ovarian Syndrome: Laparoscopic Ovarian Drilling

Objective: to review the role of surgical management of polycystic ovarian syndrome (PCOS) in infertile women with special attention to laparoscopic ovarian drilling.Design: pertinent studies and their references were identified through computer medline search.Results: to date there is no standardization of the technique of laparoscopic ovarian drilling. However, it appears that the results are promising with a high ovulation rate ranging between 70 to 90 percent, and a pregnancy rate of 70 percent.Conclusion: clomiphene citrate remains the first line of treatment to induce ovulation in infertile women with PCOS. Laparoscopic ovarian drilling can be offered to clomiphene resistant women especially to those who have also failed to respond to gonadotrophin treatment. It appears that the pregnancy rate after ovarian drilling is comparable to that of gonadotrophin therapy. However, until more complete and long term data are available, caution must be exercised when offering this type of treatment. The possible risks of the procedure are adhesion formation and premature ovarian failure. Standardization of the technique is still needed.     

Superovulation strategy before in vitro fertilization

This chapter reviews current understanding of the control of spontaneous preovulatory follicular development in the natural ovarian cycle as a basis for the design and use of superovulation strategy before clinical IVF. The principles, limitations and practical aims of therapy using clomiphene citrate and HMG to stimulate multiple follicular development are outlined together with details of methods in current use to monitor ovarian response to these drugs and to time ovulation induction and egg collection with HCG. Examples of successful IVF treatment cycles are given. It is stressed that properly controlled clinical trials to judge the relative merits of the various superovulation methods in current use for IVF have not been undertaken. Possible new approaches to ovarian stimulation before IVF include the use of 'pure' FSH, LHRH and pulsatile gonadotrophin administration.     

Effect of microsurgical resection of the ovary on fertility in patients with polycystic ovary resistant to clomiphene citrate]

Thirteen patients with clomiphene citrate resistant polycystic ovary syndrome (PCO-CR) were documented by clinical and endocrine profile. Exogenous gonadotropins (HMG, hFSH, hCG), or gonadotrophin releasing hormone agonist (GnRHa) plus gonadotropins represent a new approach to induce ovulation in these (PCO-CR) patients. 92% of these patients ovulated with exogenous gonadotropin, nevertheless the pregnancy rate was only 53%. Five out seven PCO-RC patients did not achieve pregnancy with exogenous gonadotrophins, but they did after ovarian wedge resection. It is interesting to note that four of these patients achieved their second and third pregnancy without any therapy. The authors conclude that the ovarian wedge resection may had to improve in the quality of ovulation in this very selective group of infertile patients.     

Effects of ovulation induction agents on ovarian surface epithelium in rats

The aim of this study was to examine the effects of ovulation induction agents on the ovarian surface epithelium in rats. Sixty adult females were randomly divided into six groups, each containing 10 rats. In four of these groups ovulation induction was applied with six cycles of clomiphene citrate, human menopausal gonadotrophin (HMG), recombinant FSH (rFSH) or human chorionic gonadotrophin (HCG), respectively, followed by unilateral oophorectomy, and another six cycles of the same treatment. After a total of 12 cycles of ovulation induction, the remaining ovary was taken out and the alterations in ovarian surface epithelium were examined. No malignancies were observed on the ovarian surface epithelium of the rats that were given clomiphene citrate, rFSH or HMG as ovulation induction agents, while identification rates of histopathological parameters constituting epithelial dysplasia were found to be significant (P < 0.05). There was no significant dysplasia in the epithelium of the group which was given HCG only, relative to control groups. The findings suggest that the ovulation induction agents except for HCG bring about dysplasia in the ovarian surface epithelium. It is not clear whether these dysplasias are precursory lesions of ovarian malignancies.     

Metformin therapy improves ovulatory rates, cervical scores, and pregnancy rates in clomiphene citrate-resistant women with polycystic ovary syndrome.

OBJECTIVE: To evaluate the effect of metformin therapy on hyperandrogenism, insulin resistance, cervical scores, ovulation, and pregnancy rates in clomiphene citrate-resistant women with polycystic ovary syndrome (PCOS). DESIGN: Prospective, randomized, double-blind, placebo-controlled study. SETTING: Infertility clinic of a tertiary referral center. PATIENT(S): Fifty-six women with clomiphene citrate-resistant PCOS. INTERVENTION(S): Two cycles of oral metformin therapy (850 mg, twice daily) in group I and placebo therapy (twice daily) in group II. Clomiphene citrate (100 mg/day) on cycle days 3-7 of the second cycle in both groups. MAIN OUTCOME MEASURE(S): Insulin, T, DHEAS, FSH, LH, body mass index (BMI), waist-to-hip ratio, endometrial thickness, cervical score, ovulation, and pregnancy rates in clomiphene-induced cycles after metformin therapy. Result(s): Metformin therapy resulted in a significant decrease in total T, LH level, LH/FSH ratio, insulin resistance, and mean BMI. No difference in waist-to-hip ratio, DHEAS level, and fasting insulin level was observed. Clomiphene citrate induction resulted in higher ovulation rates and thicker endometrium in the metformin group than in the placebo group. There was higher cumulative pregnancy rate in the metformin group; however, there was no significant difference in the pregnancy rate between the two groups. CONCLUSION(S): Metformin therapy not only decreases hyperandrogenism and insulin resistance but also improves ovulation rates, cervical scores, and pregnancy rates in clomiphene citrate-resistant women with PCOS.     

Polycystic ovary syndrome and ovulation induction

Before initiating treatment to induce ovulation in cases of PCOS, an appropriate evaluation of the patient and her partner, based on individual considerations, is important to optimize outcome. For obese patients with PCOS, weight-loss measures should be pursued before pharmacologic treatment is initiated. For most patients, the pharmacologic agent of choice to induce ovulation is clomiphene citrate, alone or in combination with a glucocorticoid. Treatment with metformin, alone or in combination with clomiphene citrate, may also be beneficial. For patients not responsive to clomiphene citrate, injectable gonadotropin treatment is usually warranted, although, depending on individual circumstances, laparoscopic ovarian drilling may be appropriate.     

Polycystic Ovary Syndrome: Fertility Management

Polycystic ovary syndrome (PCOS) is characterized by a series of symptoms, including oligomenorrhea or amenorrhea anovulation or infertility; it is associated with insulin resistance and compensatory hyperinsulinemia. Several treatment options are available for women with anovulatory infertility related to PCOS. Clomiphene citrate (CC) is the first-choice for induction of ovulation in PCOS patients. Laparoscopic ovarian drilling (LOD) or gonadotropin ovarian stimulation can be offered after failure of CC to achieve pregnancy. Hyperinsulinemia related to PCOS can be corrected by weight loss or insulin-sensitizing agents, such as metformin, which alone or in combination with other agents are capable of restoring ovulation. Only very limited clinical data are available on the use of letrozole at present, so letrozole cannot be recommended for routine use in ovulation induction. When all treatments fail, in vitro fertilization and embryo transfer (IVF/ET) can be tried and can have excellent results. Many treatment options available today ensure that the majority of women who are subfertile due to PCOS can be treated successfully.     

Ovulation induction--optimizing results and minimizing risks

The aim of ovulation induction therapy should be, wherever possible, to correct the underlying disturbance and achieve safe, repeated unifollicular ovulation to achieve the live birth of singleton babies. This article outlines the main causes of anovulatory infertility but deals mostly with the management of anovulatory polycystic ovary syndrome (PCOS), which is the most common problem to confront specialists in reproductive medicine. PCOS is associated with insulin resistance, particularly in those who are overweight. Thus, strategies to achieve weight loss and improve insulin sensitivity, including the use of drugs such as metformin, enhance reproductive function. Therapies to induce ovulation involve first the use of the anti-oestrogen clomiphene citrate. For those who fail to ovulate in response to clomiphene citrate, the principal options include parenteral gonadotrophin therapy or laparoscopic ovarian diathermy.     

多囊卵巢综合征手术治疗的利与弊

多囊卵巢综合征是育龄期妇女最常见的一种内分泌紊乱性疾病,排卵障碍是该类患者不育的主要原因,常用解决方法为促排卵治疗。促排卵药物,例如氯米芬临床效果好,普遍采用。但是,部分患者耐药。手术治疗,特别是腹腔镜下卵巢打孔术是目前用于氯米芬耐药的多囊卵巢综合征患者促排卵治疗的二线治疗方案,本文就卵巢手术的主要方式、腹腔镜下卵巢打孔术的适应人群、术后效果及手术并发症进行简单概括。     

GnRH-a治疗难治性排卵障碍不孕患者的初步观察

目的探讨常规诱导排卵失败后应用促性腺激素释放激素激动剂(GnRH-a)诱导排卵的临床效果.方法对常规促排卵治疗(氯米芬和HMG)失败的13例排卵障碍不孕患者,其中多囊卵巢综合症(PCOS)5例,小卵泡排卵8例.采用GnRH-a+HMG治疗,并于周期第8天开始B超监测卵泡发育并测定尿LH,当卵泡平均径线达18 mm或尿LH(+)时,给HCG诱发排卵.结果13例患者采用GnRH-a+HMG治疗19个周期,均有优势卵泡发育,其中16个周期(84.2%)卵泡平均径线达18 mm时尿LH仍为(-),给HCG诱发排卵;3个周期提前出现LH峰,取消使用HCG.36.8%的周期为单卵泡发育,75.0%为＜3个优势卵泡,8.3%为4～10个,18.8%为＞10个.妊娠率58.3%,周期妊娠率41.2%,其中单胎4例,双胎2例,4胎1例;自然流产的发生率为14.3%.结论GnRH-a可增强PCOS患者对HMG的反应性,防止内源性LH峰早现,并有良好的妊娠率及妊娠结局,可望作为治疗PCOS及小卵泡排卵患者的二线药物;低剂量HMG可使75%的治疗周期中卵泡发育数＜3个.     

Ovulation induction for polycystic ovary syndrome

Polycystic ovary syndrome (PCOS) is the commonest cause of anovulatory infertility. Various factors influence ovarian function, and fertility is adversely affected by an individual being overweight or having high serum concentrations of LH. Strategies to induce ovulation include weight loss, oral anti-oestrogens (principally clomiphene citrate), parenteral gonadotrophin therapy and laparoscopic ovarian surgery. There have been no adequately powered randomized studies to determine which of these therapies provides the best overall chance of an ongoing pregnancy. Women with PCOS are at risk of ovarian hyperstimulation syndrome (OHSS) and so ovulation induction has to be monitored carefully with serial ultrasound scans. The recognition of an association between hyperinsulinaemia and PCOS has resulted in the use of insulin sensitizing agents, such as metformin, which appear to ameliorate the biochemical profile and improve reproductive function.     

Ovulation induction for polycystic ovary syndrome

Polycystic ovary syndrome (PCOS) is the commonest cause of anovulatory infertility. Various factors influence ovarian function, and fertility is adversely affected by an individual being overweight or having high serum concentrations of LH. Strategies to induce ovulation include weight loss, oral anti-oestrogens (principally clomiphene citrate), parenteral gonadotrophin therapy and laparoscopic ovarian surgery. There have been no adequately powered randomized studies to determine which of these therapies provides the best overall chance of an ongoing pregnancy. Women with PCOS are at risk of ovarian hyperstimulation syndrome (OHSS) and so ovulation induction has to be monitored carefully with serial ultrasound scans. The recognition of an association between hyperinsulinaemia and PCOS has resulted in the use of insulin sensitizing agents, such as metformin, which appear to ameliorate the biochemical profile and improve reproductive function.     

Gonadotrophin treatment in patients with polycystic ovary syndrome

Gonadotrophin treatment in clomiphene citrate resistant polycystic ovarian syndrome (PCOS) patients, using either low-dose step-up or low-dose step-down protocols, is highly effective to achieve singleton live births. Concomitant use of gonadotrophin releasing hormone analogues (GnRHa), which will block the endogenous feedback for monofollicular development during the low-dose step-up protocol, should not be employed. It is more difficult to induce ovulation in patients with more 'severe' PCOS, characterized by obesity and insulin resistance. There is need for optimization of starting doses for both the low-dose step-up and step-down protocols. Such optimization will prevent hyperstimulation due to a starting dose far above the FSH threshold, as well as minimize the time-consuming low-dose increments by starting with a higher dose in women with augmented FSH threshold. External validation of reported models for prediction of FSH response is warranted for tailoring and optimizing treatment for everyday clinical practice. Although preliminary, the partial cessation of follicular development, along with regression leading to atresia, lends support to the LH ceiling theory, emphasizing the delicate balance and need for both FSH and LH in normal follicular development. Future well-designed randomized controlled trials will reveal whether IVF with or without in-vitro maturation of the oocytes will improve safety and efficacy compared with classical ovulation induction strategies.     

宫颈评分监测氯菧酚胺诱发排卵的评价

本文分析33例无排卵患者应用氯菧酚胺治疗76周期中宫项评分(CS)与BBT、卵泡发育及激素参数的关系。19个周期无排卵反应,CS波动,但宫项粘液透明性状不变。57个周期有排卵反应,其中32周期停药后CS渐进增高,最高宫颈评分MCS≥8,卵泡发育好,LH峰后24h内排卵;22周期MCS<8,LH峰后卵泡不消失,形成LUF,激素测定提示停药后睾酮水平明显升高;另三个周期资料不全。结果提示停药后未见药物在宫颈水平的抗雌素效应;睾酮升高可能干扰CS并导致LUF。     

Surgical or medical treatment of polycystic ovary syndrome: a cost-benefit analysis.

With the availability of laparoscopic ovarian cautery, there has been a resurgence in interest in the surgical treatment of clomiphene citrate-resistant polycystic ovary syndrome (PCOS). Comparison of ovulation and pregnancy rates has found no difference in success rates between ovarian cautery and gonadotropin ovulation induction for such women. We have therefore compared the cost of laparoscopic ovarian cautery with that of a typical cycle of gonadotropin ovulation induction, and also found that there is little difference. Because of the potential advantages of ovarian cautery, we recommend this surgery as the next line of treatment if clomiphene citrate fails to induce ovulation in PCOS patients, before gonadotropins are introduced.     

Treatment of anovulation due to polycystic ovarian syndrome by laparoscopic ovarian electrocautery

Summary. Our experience of ovarian electrocautery for the treatment of polycystic ovarian syndrome (PCOS) in ten women is described. We found that nine responded favourably, either ovulating spontaneously or becoming more responsive to ovulation induction. There was a significant and persistent fall in serum testosterone levels, and a transient fall with subsequent rise in inhibin. We recommend that laparoscopic ovarian electrocautery is considered as an alternative to ovulation induction with gonadotrophins, in women with PCOS who fail to respond to clomiphene citrate.     

Clomiphene citrate in the twenty-first century

Clomiphene citrate is the drug most commonly prescribed for ovulation induction. It is the first choice medication in normogonadotrophic oligo/amenorrhoeic infertility (WHO group 2), essentially associated with polycystic ovaries. Anovulatory women who are responsive to clomiphene citrate should be treated for at least six cycles and the treatment should probably be limited to a maximum of 12 cycles. It is necessary to monitor at least the first cycle with ultrasonography because of the risk of multiple pregnancy and the variable response of patients to different doses of clomiphene. In addition, the risk of ovarian hyperstimulation syndrome should not be underestimated. More triplets and higher order pregnancies result from ovulation induction than from in vitro fertilization, and multiple pregnancy has many risks for both mother and babies. The role of empirical clomiphene in the treatment of unexplained infertility is debatable and the present data are inconclusive. Obesity, hyperandrogenaemia and insulin resistance are important factors in clomiphene-resistant patients. Failure to ovulate in response to clomiphene has been approached by either medical or surgical treatment. An effective alternative medical treatment is gonadotrophin injections. Treatment with metformin and the new generation of insulin-sensitizing drugs is under evaluation. The most widely used surgical treatment today is laparoscopic ovarian drilling, which appears to be as effective as gonadotrophin therapy.