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Biomedical subjects

Bart C J M Fauser

Publications and source records attributed to Bart C J M Fauser.

At least 19 recordsLinked to original sources
PubMed2007

Milder ovarian stimulation for in-vitro fertilization reduces aneuploidy in the human preimplantation embryo: a randomized controlled trial.

BACKGROUND: To test whether ovarian stimulation for in-vitro fertilization (IVF) affects oocyte quality and thus chromosome segregation behaviour during meiosis and early embryo development, preimplantation genetic screening of embryos was employed in a prospective, randomized controlled trial, comparing two ovarian stimulation regimens. METHODS: Infertile patients under 38 years of age were randomly assigned to undergo a mild stimulation regimen using gonadotrophin-releasing hormone (GnRH) antagonist co-treatment (67 patients), which does not disrupt secondary follicle recruitment, or a conventional high-dose exogenous gonadotrophin regimen and GnRH agonist co-treatment (44 patients). Following IVF, embryos were biopsied at the eight-cell stage and the copy number of 10 chromosomes was analysed in 1 or 2 blastomeres. RESULTS: The study was terminated prematurely, after an unplanned interim analysis (which included 61% of the planned number of patients) found a lower embryo aneuploidy rate following mild stimulation. Compared with conventional stimulation, significantly fewer oocytes and embryos were obtained following mild stimulation (P < 0.01 and < 0.05, respectively). Consequently, both regimens generated on average a similar number (1.8) of chromosomally normal embryos. Differences in rates of mosaic embryos suggest an effect of ovarian stimulation on mitotic segregation errors. CONCLUSIONS: Future ovarian stimulation strategies should avoid maximizing oocyte yield, but aim at generating a sufficient number of chromosomally normal embryos by reduced interference with ovarian physiology.

Adult↗
PubMed2006

Validation of a prediction model for the follicle-stimulating hormone response dose in women with polycystic ovary syndrome.

OBJECTIVE: To validate a published model for the prediction of the individual FSH response dose for gonadotropin induction of ovulation in polycystic ovary syndrome (PCOS). DESIGN: Structured, complete, and carefully monitored patient-based data collection to test the external validity of the prediction model. SETTING: Twenty-nine hospitals in The Netherlands. PATIENT(S): Eighty-five clomiphene citrate (CC)-resistant women with PCOS. INTERVENTION(S): Ovulation induction in a chronic low-dose step-up FSH regimen. MAIN OUTCOME MEASURE(S): Predicted individual FSH response dose, defined as follicle growth >10 mm in diameter on ultrasound. RESULT(S): The model, using the women's body mass index, CC response, initial serum FSH level, and initial serum insulin-to-glucose ratio was studied in the validation sample. Overall, the FSH response dose predicted by the model was higher than the observed response dose. The predictive performance of the model was poor, with an R(2) of 0.11, and the average prediction error was 35 IU. CONCLUSION(S): The external validity of the model predicting the individual FSH response dose was inadequate in women with CC-resistant PCOS undergoing ovulation induction with recombinant FSH in a low-dose step-up regimen.

Adult↗
PubMed2006

What role of estrogens in ovarian stimulation.

Estrogens and progesterone represent the key ovarian hormones produced by the developing ovulatory follicle. Serum concentrations start to rise from the mid-follicular phase onwards, coinciding with the development of the dominant follicle. Androgens are converted into estrogens by aromatase activity of the granulosa cells and secreted into the follicular fluid compartment. Their significance for oocyte maturation and fertilizing potential remains unknown. Paradoxically, serum estrogen levels are within the normal range in the majority of patients presenting with cycle abnormalities due to ovarian dysfunction. Similarly, the distribution of estradiol (E2) and follicle-stimulating hormone (FSH) levels within the normal range is comparable between normo-ovulatory controls and normogonadotropic anovulatory women. Moreover, E2 levels are only moderately correlated with luteïnizing hormone (LH), testosterone (T), androstenedione (A), sex hormone binding globulin (SHBG), the free androgen index (FAI) and finally ovarian volume as measured by ultrasound. No correlations could be found between E2 and age, body weight and cycle history and FSH. Androgen concentrations and cycle history--but not E2--were the most prominent predictors of ovarian response tot the conventional ovulation induction. Anti-estrogenic compounds like clomiphene citrate and tamoxifen have remained the first-line treatment of choice for anovulation. Certainly, CC and to a lesser extent tamoxifen have demonstrated to exhibit undesired anti-estrogenic properties at the uterine level however. However, large follow-up studies demonstrate cumulative ovulation rates around 75%, and the overall pregnancy rates of around 50%. Aromatase inhibitors, another way to interfere with estrogen feedback, represent a feasible option. This claim should, however, be substantiated by further sufficiently powered, controlled studies, and the possibility of embryo toxicity remains a major concern. In retrospect, CC and tamoxifen represent the first generation of selective estrogen receptor modulators (SERMs), and many new compounds have recently been introduced into the clinic or are currently under investigation. The major focuses of these compounds are bone density, the cardiovascular system and breast cancer. No studies have been reported in the area of ovarian stimulation.

Anovulation↗
PubMed2006

The science behind 25 years of ovarian stimulation for in vitro fertilization.

To allow selection of embryos for transfer after in vitro fertilization, ovarian stimulation is usually carried out with exogenous gonadotropins. To compensate for changes induced by stimulation, GnRH analog cotreatment, oral contraceptive pretreatment, late follicular phase human chorionic gonadotropin, and luteal phase progesterone supplementation are usually added. These approaches render ovarian stimulation complex and costly. The stimulation of multiple follicular development disrupts the physiology of follicular development, with consequences for the oocyte, embryo, and endometrium. In recent years, recombinant gonadotropin preparations have become available, and novel stimulation protocols with less detrimental effects have been developed. In this article, the scientific background to current approaches to ovarian stimulation for in vitro fertilization is reviewed. After a brief discussion of the relevant aspect of ovarian physiology, the development, application, and consequences of ovarian stimulation strategies are reviewed in detail.

Aging↗
PubMed2006

Ovulation induction in normogonadotropic anovulation (PCOS).

Treatment of normogonadotropic anovulatory infertility (World Health Organization class 2, or WHO2) is by induction of ovulation using clomiphene citrate (CC), followed by follicle-stimulating hormone (FSH) in cases of treatment failure. Not all patients will become ovulatory or will conceive with this treatment. Others, exhibiting multifollicular instead of monofollicular development, may encounter complications such as ovarian hyperstimulation and multiple pregnancy. Recently introduced alternative treatment interventions-such as insulin-sensitizing drugs, aromatase inhibitors, or laparoscopic electrocautery of the ovaries-may offer the possibility of improving the efficacy of the classical ovulation induction algorithm. Based on initial patient characteristics, it may be possible to identify specific patient subgroups with altered chances of success or complications while using one of these interventions. Regarding CC and FSH ovulation induction, this has been performed using multivariate prediction models. This approach may enable us to improve safety, cost-effectiveness, and patient convenience in future ovulation induction.

Anovulation↗
PubMed2006

The early luteal phase administration of estrogen and progesterone does not induce premature luteolysis in normo-ovulatory women.

OBJECTIVE: The luteal phase after ovarian hyperstimulation for in vitro fertilization (IVF) is insufficient. Therefore, luteal phase supplementation is routinely applied in IVF. It may be postulated that premature luteolysis after ovarian hyperstimulation is due to supraphysiological steroid levels in the early luteal phase. In the present study, high doses of steroids are administered after the LH surge in normo-ovulatory volunteers in order to investigate whether this intervention gives rise to endocrine changes and a shortening of the luteal phase. DESIGN: Randomized controlled trial. METHODS: Forty non-smoking, normal weight women, between 18 and 37 years of age, with a regular menstrual cycle (24-35 days), received either high dosages of estradiol (E2), progesterone (P), E2+P or no medication. Blood sampling was performed every other day from the day of the LH surge until LH+14. Duration of the luteal phase and endocrine profiles were the main study outcomes. RESULTS: Early luteal phase steroid concentrations achieved by exogenous administration were comparable with levels observed following ovarian hyperstimulation for IVF. No difference in the luteal phase length was observed comparing all groups. However, a significant decrease in LH levels could be observed 6 days after the mid-cycle LH surge (P<0.001) in women receiving P, resulting in accelerated decrease of inhibin A production by the corpus luteum (P=0.001). CONCLUSION: The present intervention of high-dose steroid administration shortly after the LH surge failed to induce a premature luteolysis regularly in cyclic women. It seems that the induced transient suppression in LH allowed for a timely recovery of corpus luteum function. Other additional factors may be held responsible for the distinct reduction in luteal phase length observed after ovarian hyperstimulation for IVF.

Adolescent↗
PubMed2005

Individualized cost-effective conventional ovulation induction treatment in normogonadotrophic anovulatory infertility (WHO group 2).

BACKGROUND: Conventional treatment in normogonadotrophic anovulatory infertility (WHO 2) consists of clomiphene citrate (CC), followed by exogenous gonadotrophins (FSH) and IVF. Response to these treatments may be predicted on the basis of individual patient characteristics. We aimed to devise a patient-tailored, cost-effective treatment algorithm involving the above-mentioned treatment modalities, based on individual patient characteristics. METHODS: Sixteen prognostic groups are defined, according to the presence or absence of: age >30 years, amenorrhea, elevated androgen levels and obesity. The chances of response with each of the three treatments were calculated using prediction models. Treatment costs were based on the data of 240 patients visiting a specialist academic fertility unit. Outcome was an ongoing pregnancy within 12 months after initiation of treatment. The costs per pregnancy of three different strategies were compared, with a threshold for cost-effectiveness of 10 000. RESULTS: The strategy CC + FSH + IVF compared with FSH + IVF generated more pregnancies against lower costs. Compared with CC + IVF, it also produced more pregnancies, but at higher costs. For <30 years of age with normal androgen levels, costs per pregnancy were less than 10 000. For women >30 years old, costs per pregnancy were 25 000 and over 200 000, when presenting with normal or elevated androgen levels, respectively. CONCLUSIONS: The conventional treatment protocol is efficient for women aged <30 years with normal androgen levels. For women >30 years old with elevated androgen levels, FSH may be skipped.

Adult↗
PubMed2005

Patient-tailored conventional ovulation induction algorithms in anovulatory infertility.

Conventional treatment of normogonadotropic anovulatory infertility is ovulation induction using the antiestrogen clomiphene citrate, followed by follicle-stimulating hormone. Multiple follicle development, associated with ovarian hyperstimulation, and multiple pregnancy remain the major complications. Cumulative singleton and multiple pregnancy rate data after different induction treatments are needed. Newer ovulation induction interventions, such as insulin-sensitizing drugs, aromatase inhibitors and laparoscopic ovarian electrocoagulation, should be compared with conventional strategies. Ovulation induction efficiency might improve if patient subgroups with altered chances for success or complications with new or conventional techniques could be identified, using multivariate prediction models based on initial screening characteristics. This would make ovulation induction more cost-effective, safe and convenient, enabling doctors to advise patients on the most effective and patient-tailored treatment strategy.

Algorithms↗
PubMed2005

Influence of oral contraceptive pills on phenotype expression in women with polycystic ovary syndrome.

Polycystic ovarian syndrome (PCOS) is characterized by a heterogeneous phenotype including chronic anovulation, hyperandrogenism and polycystic ovaries. The use of oral contraceptive pills (OCP) alters features characteristic for the syndrome. In the present study, PCOS features were compared between women using or not using OCP at the time of the study. One hundred and one women diagnosed with normogonadotrophic anovulatory infertility were included. A total of 81 (80%) women were diagnosed with PCOS (revised 2003 criteria). From these women, a total of 54 did not use OCP, whereas 27 women did. Corrected for age, women taking OCP had increased serum concentrations of sex hormone-binding globulin (P < 0.001). Serum concentrations of testosterone (P = 0.04) and androstenedione (P = 0.01) were decreased. These differences resulted in a decreased free androgen index for women currently taking OCP compared with women without (P < 0.001). The mean ovarian volume/ovary and the mean follicle number/ovary were not different. Use of OCP influences phenotype expression (the observable trait) of individual women known to suffer from PCOS by reducing hyperandrogenism. Despite taking OCP, women still fulfilled the revised 2003 criteria for the syndrome, as PCO morphology was still present. Hence, OCP use does not appreciably affect the PCOS phenotype.

Adult↗
PubMed2005

Does metformin modify ovarian responsiveness during exogenous FSH ovulation induction in normogonadotrophic anovulation? A placebo-controlled double-blind assessment.

OBJECTIVE: To assess whether the addition of metformin to gonadotrophin ovulation induction in insulin-resistant, normogonadotrophic, anovulatory women alters ovarian responsiveness to exogenous FSH. DESIGN: Placebo-controlled double-blind assessment in an academic hospital. RESULTS: After a progestagen withdrawal bleeding, patients were randomised for either metformin (n = 11) or placebo (n = 9) treatment. In cases of absent ovulation, exogenous FSH was subsequently administered to induce ovulation. Only during metformin treatment did body mass index and androgen (androstenedione and testosterone) levels decrease, whereas FSH and LH levels increased significantly. In the metformin group, a single patient ovulated before the initiation of exogenous FSH. Significantly more monofollicular cycles and lower preovulatory oestradiol concentrations were observed in women receiving FSH with metformin compared with FSH alone. CONCLUSIONS: Metformin co-treatment in a group of insulin-resistant, normogonadotrophic, anovulatory patients resulted in normalization of the endocrine profile and facilitated monofollicular development during the FSH induction of ovulation.

Adolescent↗
PubMed2005

Relationship between inhibin A and B, estradiol and follicle growth dynamics during ovarian stimulation in normo-ovulatory women.

OBJECTIVE: To investigate the relationship between serum concentrations of inhibin A, inhibin B and estradiol (E(2)) and the number of developing follicles during the administration of exogenous follicle-stimulating hormone (FSH) in various regimens in normo-ovulatory volunteers and to evaluate if inhibins act as suitable markers for the number of developing follicles during ovarian stimulation. DESIGN AND METHODS: Serial hormone determinations and assessment of follicle numbers were carried out during unstimulated cycles and during various interventions with exogenous FSH. Subjects were randomized for FSH administration into the following groups: a single high dose (375 IU) during the early follicular phase (group A), 5 consecutive low doses (75 IU/day) starting in the mid follicular phase (group B) or daily low doses (75 IU/day) during the early to late follicular phase (starting on cycle days 3, 5 or 7; groups C, D and E respectively). RESULTS: Extending the FSH window increases the number of small antral follicles and hence inhibin B serum concentrations. If such an intervention results in multi-follicular growth, mid follicular phase inhibin B (P = 0.001) as well as late follicular phase inhibin B and inhibin A levels are significantly (P < 0.05 and P < 0.01 respectively) increased compared with mono-follicular cycles or the natural cycle. Although mid follicular inhibin B levels correlated well with the number of small antral (P < 0.05) and pre-ovulatory (P < 0.001) follicles in the late follicular phase, mid follicular inhibin A and estradiol serum concentrations only correlated with the number of pre-ovulatory follicles (P < 0.001 and P < 0.01 respectively). CONCLUSIONS: The present data extend our understanding of the relationship between follicle dynamics, serum inhibins and FSH during ovarian hyperstimulation. However, although mid follicular inhibin B does correlate with the number of developing follicles, it does not facilitate the identification of women at risk for multiple follicle development.

Adult↗
PubMed2004

Abnormal gene expression profiles in human ovaries from polycystic ovary syndrome patients.

Polycystic ovary syndrome (PCOS) represents the most common cause of anovulatory infertility and affects 5-10% of women of reproductive age. The etiology of PCOS is still unknown. The current study is the first to describe consistent differences in gene expression profiles in human ovaries comparing PCOS patients vs. healthy normoovulatory individuals. The microarray analysis of PCOS vs. normal ovaries identifies dysregulated expression of genes encoding components of several biological pathways or systems such as Wnt signaling, extracellular matrix components, and immunological factors. Resulting data may provide novel clues for ovarian dysfunction in PCOS. Intriguingly, the gene expression profiles of ovaries from (long-term) androgen-treated female-to-male transsexuals (TSX) show considerable overlap with PCOS. This observation provides supportive evidence that androgens play a key role in the pathogenesis of PCOS. Presented data may contribute to a better understanding of dysregulated pathways in PCOS, which might ultimately reveal novel leads for therapeutic intervention.

Adult↗
PubMed2004

Changes in anti-Müllerian hormone serum concentrations over time suggest delayed ovarian ageing in normogonadotrophic anovulatory infertility.

BACKGROUND: Anti-Müllerian hormone (AMH), produced by growing pre-antral and early antral ovarian follicles, has been shown to be a useful marker for ovarian ageing. Serum AMH concentrations are elevated during reproductive life in anovulatory women, especially in those patients exhibiting polycystic ovaries (PCO). The current study was designed to investigate whether the decrease in AMH serum concentrations over time is different comparing women with normogonadotrophic anovulation [World Health Organization (WHO) group 2 (including polycystic ovary syndrome (PCOS)] and normo-ovulatory controls. METHODS AND RESULTS: AMH serum levels were assessed on two occasions in 98 patients suffering from WHO 2 anovulatory infertility as well as in 41 normo-ovulatory premenopausal women. Median time interval between both visits was 2.6 years (range 0.3-9.0) for WHO 2 patients compared with 1.6 years (range 1.0-7.3) in controls. Serum AMH concentrations were significantly (P < 0.0001) elevated on both occasions in WHO 2 patients (AMH1, median = 7.5 microg/l, range 0.1-35.8; and AMH2, median = 6.7 microg/l, range 0.0-30.6) compared with controls (AMH1, median = 2.1 microg/l, range 0.1-7.4; and AMH2, median = 1.3 microg/l, range 0.0-5.0). Regression analysis, corrected for age, indicated a significant relative decrease in serum AMH concentrations over time for both groups (P < 0.001). However, the decline in serum AMH in WHO 2 patients was significantly less compared with controls (P = 0.03). CONCLUSION: The present longitudinal study shows that serum AMH concentrations decrease over time both in women presenting with WHO 2 anovulatory infertility and in normo-ovulatory controls. The decrease in WHO 2 patients is less pronounced despite distinctly elevated concentrations. This observation may suggest retarded ovarian ageing and hence a sustained reproductive life span in these patients.

Adolescent↗
PubMed2004

Reproductive biology and IVF: ovarian stimulation and endometrial receptivity.

The influence of ovarian stimulation on endometrium receptivity has been inadequately addressed in medical literature. Hormonal effects of ovarian stimulation on endometrial changes as compared with the natural cycle should be elucidated and correlated with the potential of the embryo to implant. It is important to distinguish between the endometrial effect of induction of ovulation in anovulatory women and those of ovarian (super)ovulation in ovulatory women. Induction of ovulation leads to in vivo conception whereas ovarian stimulation results in in vitro fertilization. The available data in the field indicate that endometrial changes have an impressive negative influence on the potential of embryonic implantation. The aim of this review is to analyse the effects of gonadotropin, GnRH-agonist and GnRH-antagonist administration on endometrial behaviour, to highlight the gaps in current knowledge and to propose areas in which research is needed.

Clomiphene↗
PubMed2004

Anti-Müllerian hormone expression pattern in the human ovary: potential implications for initial and cyclic follicle recruitment.

Anti-Müllerian hormone (AMH) is a member of the transforming growth factor-beta superfamily, which plays an important role in both ovarian primordial follicle recruitment and dominant follicle selection in mice. However, the role of AMH in folliculogenesis in humans has not been investigated in detail. In the present study, AMH expression was assessed using immunohistochemistry in ovarian sections, obtained from healthy regularly cycling women. To this end, a novel monoclonal antibody to human AMH was developed. AMH expression was not observed in primordial follicles, whereas 74% of the primary follicles showed at least a weak signal in the granulosa cells. The highest level of AMH expression was present in the granulosa cells of secondary, preantral and small antral follicles <or=4 mm in diameter. In larger (4-8 mm) antral follicles, AMH expression gradually disappeared. In conclusion, in the human AMH expression follows a similar pattern as compared to the mouse and rat, suggesting an important role of AMH in folliculogenesis.

Adolescent↗