Ovulationshemmer bei Risikogruppen

Severe adverse effects during the use of ovulation inhibitors occur mostly in women who have an elevated risk for the development of certain diseases owing to hereditary or acquired factors. By means of a careful personal or family history analysis as well as specific laboratory examinations, an existing predisposition may frequently be diagnosed and the individual risk associated with the use of oral contraceptive inhibitors may be estimated. The present contribution describes the potential effects of treatment with ovulation inhibitors on women with thrombophilia, cardiovascular disease, diabetes mellitus, dyslipidemia, overweight or underweight, tumors, psychiatric and neurological diseases and autoimmune disease. The hormonal methods and non-hormonal alternatives available for contraception are elucidated according to existing lesions and risk factors and the advantages and disadvantages are discussed.     

Aromatase inhibition for ovarian stimulation: future avenues for infertility management

Ovarian stimulation is applied during infertility management either alone or in conjunction with intrauterine insemination and assisted reproductive technologies. At the present time, the two main medications used for ovarian stimulation include an oral antiestrogen, clomiphene citrate, and injectable gonadotropins. In spite of the high ovulation rate with the use of clomiphene citrate, the pregnancy rate is much lower. In clomiphene citrate failures, gonadotropin injections have generally been used as the next treatment option. Treatment with gonadotropins is difficult to control and characteristically associated with increased risk of severe ovarian hyperstimulation syndrome and high multiple pregnancies. Therefore, an effective oral treatment that could be used without risk of hyperstimulation and with minimal monitoring is the preferred therapy. We hypothesize that aromatase inhibitors can be administered early in the follicular phase to induce ovulation by releasing the hypothalamus or pituitary from estrogen negative feedback. Based on this hypothesis, we have reported the success of aromatase inhibitors in induction and augmentation of ovulation in addition to improving ovarian response to gonadotropin stimulation. Moreover, there are other potential applications for aromatase inhibitors in infertility management, including improving implantation in assisted reproduction and in-vitro maturation.     

Aromatase inhibitors in ovulation induction

The new third generation aromatase inhibitors are extremely potent and specific oral inhibitors of estrogen production. We reported the success of using aromatase inhibitors for induction of ovulation in World Health Organization (WHO) type II anovulatory patients. Promising pregnancy rates were associated with the use of aromatase inhibitors for induction of ovulation in these women. In addition, the use of aromatase inhibition in conjunction with gonadotropin injection was associated with a significant reduction in the gonadotropin dose required for optimum controlled ovarian hyperstimulation. We believe that these oral agents are efficient and safe and have many advantages compared with clomiphene citrate (CC). We propose that aromatase inhibitors will replace CC in the future as the new primary treatment for ovulation induction. In this review, we present an update on the use of aromatase inhibitors for induction of ovulation and we discuss several new areas of potential interest regarding the use of aromatase inhibitors, either alone or together with recombinant follicle-stimulating hormone (FSH) for infertility treatment. Further research in these areas may demonstrate an expanded role in assisted reproductive technologies.     

Ovulation induction management of PCOS

Ovulation induction is the principal infertility treatment for women with polycystic ovarian syndrome (PCOS). Among PCOS patients who are overweight or obese, weight loss is the most physiologic method of inducing ovulation. For women in whom weight loss is not possible, or for lean women with PCOS, clomiphene citrate is an effective first-line method of ovulation induction. In clomiphene-resistant women, alternative treatments include adjunctive metformin or dexamethasone, aromatase inhibitors, or ovarian drilling. If there is no pregnancy despite several cycles of successful ovulation induction, gonadotropin treatment should be considered, in which case in vitro fertilization is recommended as the safest and most effective strategy.     

Consensus on infertility treatment related to polycystic ovary syndrome

The treatment of infertile women with polycystic ovary syndrome (PCOS) is surrounded by many controversies. On the basis of the currently available evidence, a group of experts reached a consensus regarding the therapeutic challenges raised in these women. Before any intervention is initiated, preconceptional counseling should be provided emphasizing the importance of lifestyle, especially weight reduction and exercise in overweight women, smoking, and alcohol consumption. The recommended first-line treatment for ovulation induction remains the anti-estrogen clomiphene citrate (CC). Recommended second-line intervention, should CC fail to result in pregnancy, is either exogenous gonadotropins or laparoscopic ovarian surgery (LOS). The use of exogenous gonadotropins is associated with increased chances for multiple pregnancy, and, therefore, intense monitoring of ovarian response is required. Laparoscopic ovarian surgery alone is usually effective in less than 50% of women, and additional ovulation induction medication is required under those circumstances. Overall, ovulation induction (representing the CC-gonadotropin paradigm) is reported to be highly effective with a cumulative singleton live-birth rate of 72%. Recommended third-line treatment is in vitro fertilization (IVF). More patient-tailored approaches should be developed for ovulation induction based on initial screening characteristics of women with PCOS. Such approaches may result in deviation from the above mentioned first-line, second-line, or third-line ovulation strategies in well-defined subsets of patients. Metformin use in PCOS should be restricted to women with glucose intolerance. Based on recent data available in the literature, the routine use of this drug in ovulation induction is not recommended. Insufficient evidence is currently available to recommend the clinical use of aromatase inhibitors for routine ovulation induction. Even singleton pregnancies in PCOS are associated with increased health risk for both the mother and the fetus.     

Aromatase Inhibitors: Potential Reproductive Implications

MEDLINE, EMBASE, Scopus, and Web of Science databases literature search from inception to March 2009 was performed to identify published clinical trials and cohort, observational, and in vitro studies that evaluated the use of aromatase inhibitors in reproductive medicine for indications other than ovulation induction. Aromatase inhibitors are currently being investigated for breast cancer prevention in women at high risk. Aromatase inhibitors may be used for treatment of symptomatic myomas and endometriosis as an alternative to surgical intervention. Current evidence does not support the routine use of aromatase inhibitors for these conditions without prospective controlled trials. Aromatase inhibitor cotreatment can be used to prevent the initial estrogen flare effect of gonadotropin-releasing hormone agonist treatment to offer flexibility in initiating this therapy.     

New advances in ovulation induction

PURPOSE OF REVIEW: To review recent advances in ovulation induction. RECENT FINDINGS: Aromatase inhibitors can replace clomiphene citrate as ovulation-inducing substances. The most widely used aromatase inhibitor for this purpose is letrozole and the optimal dose is 5 mg daily for 5 days. Compared to clomiphene citrate, it is associated with a thicker endometrium and a better pregnancy rate. It is as effective as gonadotropin but yet less expensive. The overall rates of congenital malformation among newborns conceived after infertility treatment with letrozole or clomiphene citrate are similar. When letrozole is combined with gonadotropin, it leads to lower gonadotropin requirements with pregnancy rates comparable to gonadotropin treatment alone. Another promising aromatase inhibitor is anastrazole. Recent evidence suggests that luteinizing hormone activity in human menopausal gonadotropin modifies follicular development so that fewer intermediate-sized follicles develop. Compared to the use of follicular stimulating hormone only, human menopausal gonadotropin is associated with less ovarian hyperstimulation. SUMMARY: Aromatase inhibitors are alternative drugs to clomiphene or gonadotropin for ovulation induction or superovulation.     

Polycystic ovary syndrome and ovulation induction

Polycystic ovary syndrome (PCOS) is likely the most common cause of anovulatory infertility. Although many options are available for ovulation induction in these patients, there is currently no evidence-based algorithm to guide the initial and subsequent choices of ovulation induction methods. In obese women with PCOS, mild to moderate weight loss results in improvement of ovulatory dysfunction, and should be advocated at the onset of the evaluation. Clomiphene citrate is currently the 1st line medical therapy for ovulation induction. Glucocorticoids do not result in consistent ovulation and have significant side effects. Exogenous pulsatile GnRH treatment has low ovulation and pregnancy rates with a high risk of miscarriage. The most commonly used medical agents for ovulation induction in clomiphene-resistant women with PCOS are parenteral gonadotropins. Various gonadotropin preparations and different protocols are available; however the risk of multiple pregnancy and ovarian hyperstimulation is high with gonadotropin therapy. The frequent association between PCOS and insulin resistance has prompted recent studies on the effect of insulin-sensitizing agents on spontaneous and as an adjuvant to conventional ovulation induction therapies. Overall, the improvement in ovulation with insulin sensitizing drugs is modest, and unresolved issues such as variability in ovarian response remain to be addressed in future studies. Nevertheless, these agents may be beneficial in a subset of PCOS patients. Surgical ovulation induction methods such as ovarian diathermy have been reported to be moderately effective. However, due to the inherent associated risks and unknown effect on long-term reproductive potential, this modality should be reserved for patients who are clomiphene-resistant and unable or unwilling to proceed to gonadotropin therapy.     

Psychological aspects of premenstrual syndrome

Premenstrual syndrome (PMS) is a group of psychological and physical symptoms which regularly occur during the luteal phase of the menstrual cycle and resolve by the end of menstruation. The severe and predominantly psychological form of PMS is called premenstrual dysphoric disorder (PMDD). The exact aetiology of PMS is not known. PMS results from ovulation and appears to be caused by the progesterone produced following ovulation in women who have enhanced sensitivity to this progesterone. The increased sensitivity may be due to neurotransmitter (mainly serotonin) dysfunction. The key diagnostic feature is that the symptoms must be absent in the time between the end of menstruation and ovulation. Prospective symptom rating charts are used for this purpose. Treatment is achieved by suppression of ovulation or reducing progesterone sensitivity with selective serotonin re-uptake inhibitors. In this chapter, the authors describe the aetiology, symptoms, diagnosis and evidence-based management of premenstrual syndrome.     

Induction of ovulation

Anovulatory infertility is one of the commonest causes of infertility and can be caused by problems related to the ovary (normogonadotropic and hypergonadotropic hypogonadism) or the pituitary and hypothalamus (hypogonadotropic hypogonadism). Consequently induction of ovulation will depend on the cause of infertility. For those with normogonadotropic hypogonadism, ovulation can be induced using antioestrogens such as clomifene citrate and tamoxifen or aromatase inhibitors such as letrozole. Second line treatments include metformin, gonadotropins and laparoscopic ovarian drilling. Those with hypogonadotropic hypogonadism will require gonadotropins or GnRH analogues. The following review outlines the different approaches to ovulation induction with a focus on commonly encountered clinical scenarios.     

Thrombophilias and gynaecology

In gynaecology, women are exposed to sex steroids when using oral contraceptives, hormone replacement therapy or when undergoing in vitro fertilization treatment and ovulation induction. Oral contraceptives and the use of hormone replacement therapy increase the risk of venous thrombosis. The risk is highest in the first year of use and higher among women with clotting defects. Women taking third-generation oral contraceptives have an almost twofold increased risk of venous thrombosis compared with those taking second-generation oral contraceptives. Inherited clotting defects, which are themselves risk factors of venous thrombosis, (e.g. factor V Leiden mutation, deficiency of protein C, protein S or antithrombin, high plasma levels of factor VIII, and prothrombin mutation) appear synergistically increase the risk of venous thrombosis caused by oral contraceptives. Recent studies also point to an interaction between hormone replacement therapy and coagulation defects in causing venous thrombosis. Emerging studies show that in vitro fertilization treatment and ovulation induction are also risk factors for venous thrombosis; the role of coagulation defects in this association is not yet clear.     

Diagnosis and management of endometrial hyperplasia

Endometrial hyperplasia (EH), with or without atypia, is a common gynecologic diagnosis and a known precursor of endometrial carcinoma, the most common gynecologic malignancy. During the reproductive years, the risk of EH is increased by conditions associated with intermittent or absent ovulation, in particular, polycystic ovary syndrome. After menopause when ovulation has ceased, EH is more common in women with conditions that increase levels of circulating estrogen such as obesity or estrogen replacement therapy. Women with EH are at increased risk for both concurrent and subsequent endometrial cancer. The risk of coexisting cancer in women with a diagnosis of EH at endometrial sampling is due to limitations in both endometrial sampling and the diagnostic reproducibility among pathologists. These diagnostic uncertainties add to the complexity of managing EH. This review offers a rational approach to prevention, diagnosis, and treatment of EH, including hormone therapy and conservative surgical methods.     

辅助生殖技术相关血栓性疾病的防治

辅助生殖技术(ART)并发血栓性疾病的报道逐年增加,口服避孕药(OCs)、促排卵药物的应用、卵巢过度刺激综合征(OHSS)以及多胎妊娠是血栓性疾病发生的高危因素。在促排卵治疗过程中,应高度警惕高危人群血栓性疾病的发生,早期诊断并积极治疗。血栓性疾病的发生重在预防。对于既往有血栓病史或血栓家族史的高危患者必要时可行相关易栓症的遗传性筛查。     

Ovulation induction

In the woman with anovulation and polycystic ovarian syndrome, there are many options for ovulation induction. Treatment should be individualized, but clomiphene citrate is an excellent first-line agent. In the woman resistant to clomiphene citrate, combination therapy often results in pregnancy. Some women with PCOS only respond to gonadotropin therapy. These women are at a higher risk for multiple pregnancy and ovarian hyperstimulation syndrome. In the woman with anovulation and hypothalamic amenorrhea, the options for ovulation induction are limited. The luteal phase must be supported. The hypothalamus is unable to support the corpus luteum or early pregnancy.     

人工授精周期诱导排卵药物及方案的研究进展

诱导排卵联合宫腔内人工授精是广泛应用的一项辅助生育技术。诱导排卵目的是形成单一卵泡的发育成熟,尽可能地减少发生多胎妊娠和卵巢过度刺激综合征的风险。抗雌激素类和芳香化酶抑制剂因口服方便而广泛应用,单独使用妊娠率较低。促性腺激素类药物可以获得较高的临床妊娠率,采用小剂量递增的温和方案不但能够保证较高的单卵泡发育还能够明显的减少并发症的发生。关于促性腺激素促排卵治疗中卵巢反应预测因子还有待于进一步研究。     

Ovulation induction in polycystic ovary syndrome

Management of polycystic ovary syndrome (PCOS) usually spans a woman's reproductive years. While treatment of androgenic symptoms is often a primary concern, periodically, the regimen has to be modified because of a desire for pregnancy. As these women are usually anovulatory, ovulation induction is generally required. The premise on which ovulation induction in PCOS is based is two-fold: increasing ovarian exposure to follicle stimulating hormone (FSH) and/or correcting hormonal derangements. Potential differences in pathogenesis, evidenced clinically by phenotypic diversity, suggest that treatment should be individualized. This paper is an overview of treatments available and also provides a critical appraisal of management options. These options include the use of clomiphene citrate, insulin sensitizers, and the combination. Protocols for ovulation induction with FSH injections are outlined and the relative risks of multiple gestation and severe ovarian hyperstimulation syndrome of these various protocols discussed. The use of aromatase inhibitors and the occasional use of glucocorticoids are briefly reviewed. Finally, the role of laparoscopic ovarian diathermy in the management of anovulatory infertility in PCOS is outlined.     

Aromatase inhibitors--is it a new opportunity in the treatment of infertility?

Aromatase P-450 is a key enzyme in the production of estrogens, that is, the conversion of androstenedione and testosterone to estrone and estradiol. Aromatase is a good target for selective inhibition. New aromatase inhibitors provide a good opportunity for successful treatment during infertility management. They have a potential to replace clomiphene citrate (CC) as the first-line treatment for ovulation induction. Applying aromatase inhibitors during assisted reproduction followed: reducing the FSH dose needed to achieve optimum controlled ovarian hyperstimulation (COH); improving ovarian response to FSH in poor responders; terminating positive feedback loop and improving ovarian response to COH in infertile case with endometriosis; improving implantation rates in assisted reproduction technology (ART); reducing estrogen levels to reduce the risk of OHSS during COH.     

Three decades after Gjönnaess’s laparoscopic ovarian drilling for treatment of PCOS; what do we know? An evidence-based approach

Background

The introduction of laparoscopic ovarian drilling (LOD) by Gjönnaess in 1984 as a substitute for ovarian wedge resection created opportunities for extensive research given its worldwide application for ovulation induction in women with polycystic ovary syndrome (PCOS).

Purpose

To critically evaluate and summarize the current body of literature regarding the role of LOD for the management of PCOS entailing its different preoperative, operative and postoperative aspects. In addition, long-term efficacy, cost-effectiveness, patient preference and health-related quality of life issues will be evaluated together with other available alternatives of ovulation induction treatments.

Methods

A PubMed search was conducted looking for the different trials, reviews and various guidelines relating to the role of LOD in the management of PCOS.

Results

LOD whether unilateral or bilateral is a beneficial second-line treatment in infertile women with clomiphene citrate (CC)-resistant PCOS. It is as effective as gonadotrophin treatment but without the risk of multiple pregnancy or ovarian hyperstimulation and does not require intensive monitoring. Increased responsiveness of the ovary to CC especially in patients who remain anovulatory following LOD is another advantage. Recent evidence suggests that relatively novel oral methods of ovulation induction, e.g. CC plus metformin, CC plus tamoxifen, rosiglitazone plus CC and aromatase inhibitors represent a successful alternative to LOD in CC-resistant PCOS. Meanwhile current evidence does not support LOD as a first-line approach in PCOS-related anovulation or before IVF.

Conclusion

LOD is currently recommended as a successful and economical second-line treatment for ovulation induction in women with CC-resistant PCOS.     

Advances in the understanding of risk factors for ovarian cancer

The identification of risk factors for ovarian cancer is central to the goal of preventing deaths from this disease. Reproductive and hormonal history clearly modulate the risk of ovarian cancer. Continuous ovulation associated with nulliparity increases the likelihood of ovarian malignancy. Protective factors include conditions that suspend ovulation, such as pregnancy, lactation and oral contraceptive use. Hereditary syndromes account for 10% of ovarian cancer cases. The breast ovarian cancer syndrome is caused by mutations in the BRCA1 and BRCA2 genes and is associated with an 11-40% risk of developing ovarian cancer. The hereditary nonpolyposis colorectal cancer syndrome (HNPCC, or Lynch II) is caused by mutations in DNA mismatch repair genes and carries a 12% risk of ovarian cancer. Due to a lack of adequate screening techniques, women with BRCA1, BRCA2 or HNPCC mutations should consider prophylactic removal of the ovaries and fallopian tubes when childbearing is complete. Genetic polymorphisms are hereditary genetic variations that may act in concert with other genetic, hormonal or environmental factors to potentiate the risk of ovarian cancer. Finally, ovarian cancer risk is altered by environmental and behavioral factors. Further study of the risk factors for ovarian cancer is needed to develop effective preventive strategies.     

Gonadotrophin regimens and oocyte quality in women with polycystic ovaries

The systemic endocrine environment during the later stages of follicle development has a crucial role in co-ordinating follicular and oocyte maturation before ovulation. Polycystic ovary syndrome (PCOS) is associated with abnormal circulating hormones, abnormal peri-follicular vascularity and significant abnormalities of granulosa cell function. After induction of ovulation, fertilization rates in vivo in women with PCOS are normal, but there is an increased risk of early pregnancy loss, particularly in obese patients. After in-vitro maturation of oocytes or following ovulation induction for IVF, oocyte and embryo quality in vitro are not obviously impaired in PCOS. In some reports however, specific endocrine abnormalities, such as hyperinsulinaemia/insulin resistance, have been noted to be associated with reduced fertilization rates and abnormal early embryonic development.