Fauser, B.C.J.M.

The phenotype of polycystic ovary syndrome ameliorates with aging (Article)

2011-11-01T00:00:00Z

Objective: To assess the effects of aging on the features of polycystic ovary syndrome (PCOS). Design: Retrospective longitudinal follow-up study. Setting: Tertiary care center. Patient(s): Patients with PCOS, diagnosed according to the 2003 Rotterdam criteria, who visited the outpatient clinic on consecutive occasions with a minimum interval of 6 months. Intervention(s): Comparisons were made between the first visit and the consecutive visit grouped by intervals. Main Outcome Measure(s): Changes in clinical and endocrine characteristics. Result(s): A total of 254 women visited the outpatient clinic on 2 occasions each. Consecutive visits were grouped into 0.5 to 3.9 years (n = 172; mean follow-up, 2.6 years) and 4.0 to 7.0 years (n = 82; mean follow-up, 5.5 years). At their second visit, significantly more women had regained a regular cycle. The total antral follicle count was similar. Serum levels of testosterone, androstenedione, and dehydroepiandrosterone sulfate had decreased significantly. Plasma glucose levels had increased, whereas serum insulin levels and homeostasis model assessment score had significantly decreased. Conclusion(s): The PCOS phenotype changed with aging, suggesting an amelioration of the phenotype and ovarian dysfunction as indicated by the increase in number of regular menstrual cycles, decrease in serum androgen levels, and decrease in insulin resistance.

Genetic polymorphisms of the glucocorticoid receptor may affect the phenotype of women with anovulatory polycystic ovary syndrome (Article)

2011-10-01T00:00:00Z

Background Polycystic ovary syndrome (PCOS) is characterized by ovarian dysfunction. The association with obesity and insulin resistance is well established. Steroid hormones play a central role in the regulation of both ovarian function and body composition. This study aims to assess the influence of known functional polymorphisms in genes that are responsible for the production, metabolism and signal transduction of steroid hormones on the susceptibility to and phenotype of PCOS. Methods We included 518 Caucasian women with anovulatory PCOS (2003 Rotterdam criteria) and 2996 population-based controls. Functional polymorphic variants were selected in genes that affect the production of estradiol and cortisol [aromatase (CYP19), 11-beta-hydroxysteroid dehydrogenase type I (HSD11B1) and hexose-6-phosphate dehydogenase (H6PD)] and in genes for signal transduction proteins [estrogen receptor (ESR1 and ESR2) and glucocorticoid receptor (GCR)]. Results Genotype-frequencies were similar in PCOS cases and population-based controls. We observed possible associations between GCR genotype and LH levels that suggest an inhibitory influence of GCR, i.e., lower LH levels in association with GCR alleles that are known to increase receptor sensitivity (rs6195 and rs41423247) and higher LH levels in GCR variants that may inhibit receptor sensitivity (rs6190 and rs6198). Conclusions The present study did not identify risk alleles for PCOS, although the study was limited by an absence of endocrine data for the population-based controls. However, GCR variants may influence gonadotrophin levels in women with anovulatory PCOS. We hypothesize that glucocorticoids can affect the function of the hypothalomo-pituitary-gonadal axis in humans.

Sex steroid hormones and reproductive disorders: Impact on women's health (Article)

2011-08-01T00:00:00Z

The role of sex steroid hormones in reproductive function in women is well established. However, in the last two decades it has been shown that receptors for estrogens, progesterone and androgens are expressed in non reproductive tissue /organs (bone, brain, cardiovascular system) playing a role in their function. Therefore, it is critical to evaluate the impact of sex steroid hormones in the pathophysiology of some diseases (osteoporosis, Alzheimer, atherosclerosis). In particular, women with primary ovarian insufficiency, polycystic ovary syndrome, endometriosis and climacteric syndrome may have more health problems and therefore an hormonal treatment may be crucial for these women.

A role for Aurora C in the chromosomal passenger complex during human preimplantation embryo development (Article)

2011-07-01T00:00:00Z

Background: Human embryos generated by IVF demonstrate a high incidence of chromosomal segregation errors during the cleavage divisions. To analyse underlying molecular mechanisms, we investigated the behaviour of the chromosomal passenger complex (CPC) in human oocytes and embryos. This important mitotic regulatory complex comprises the inner centromere protein (INCENP), survivin, borealin and Aurora B, or the meiotic kinase Aurora C. Methods: We analysed mRNA expression by quantitative RTPCR of all CPC members in human oocytes, tripronuclear (3PN) zygotes, 2-cell and 4-cell embryos developed from 3PN zygotes, plus good-quality cryopreserved 8-cell, morula and blastocyst stage embryos. Protein expression and localization of CPC members were investigated by immunofluorescence in oocytes and embryos arrested at prometaphase. Histone H3S10 phosphorylation was investigated as an indicator of a functional CPC. Results: INCENP, survivin and borealin were detected at the inner centromere of prometaphase chromosomes in all stages investigated. Whereas Aurora B and C are both present in oocytes, Aurora C becomes the most prominent kinase in the CPC during the first three embryonic cell cycles. Moreover, Aurora C mRNA was up-regulated with Aurora B after activation of the embryonic genome and both proteins were detected in early Day 4 embryos. Subsequently, only Aurora B was detected in blastocysts. Conclusions: In contrast to somatic cells, our Results: point to a specific role for Aurora C in the CPC during human preimplantation embryo development. Although, the presence of Aurora C in itself may not explain the high chromosome segregation error rate, the data presented here provide novel information regarding possible mechanisms.

Observer agreement in the evaluation of the uterine cavity by hysteroscopy prior to in vitro fertilization (Article)

2011-04-01T00:00:00Z

Background Hysteroscopy is known as the most accurate test for diagnosing intrauterine pathology. To optimize fertility treatment, it is increasingly common to perform hysteroscopy as a routine procedure prior to IVF. However, literature on the reproducibility of screening hysteroscopy is lacking. Therefore, the aim of the study was to assess the intra- and inter-observer agreement in the individual evaluation of the uterine cavity using video recordings of hysteroscopy procedures in asymptomatic patients prior to IVF.Methods Screening hysteroscopies of 123 unselected, asymptomatic, infertile women with an indication for IVF/ICSI treatment were recorded on DVD. After editing, the hysteroscopy performer and three other experienced gynecologists independently assessed all recordings, focusing on the appearance of predefined intrauterine abnormalities (i.e. endometrial polyps, myomas, adhesions or septa). The intra- and inter-observer agreement was calculated and expressed as perfect agreement and κ coefficient or intraclass correlation coefficient.Results In total, 123 hysteroscopy procedures were recorded. After editing and selection, based on the record quality, 107 remained for assessment and analysis. The intraobserver agreement on the appearance of any of the predefined intrauterine abnormalities was substantial (κ 0.707), whereas the interobserver agreement was moderate (κ 0.491). Perfect agreement occurred only in 77.6 of the cases. Conclusions Interobserver agreement among experienced gynecologists appeared to be rather disappointing. The latter may have implications for the diagnostic accuracy of screening hysteroscopy prior to IVF, as well as for its clinical significance in IVF programs.

Fertility and ovarian function in high-dose estrogen-treated tall women (Article)

2011-04-01T00:00:00Z

Background/Objective: High-dose estrogen treatment to reduce final height of tall girls has been shown to interfere with fertility. Ovarian function has not been studied. We therefore evaluated fertility and ovarian function in tall women who did or did not receive such treatment in adolescence. Methods: This was a retrospective cohort study of 413 tall women aged 23-48 yr, of whom 239 women had been treated. A separate group of 126 fertile, normoovulatory volunteers aged 22-47 yr served as controls. Results: Fertility was assessed in 285 tall women (157 treated, 128 untreated) who had attempted to conceive. After adjustment for age, treated women were at increased risk of experiencing subfertility [odds ratio (OR) 2.29, 95% confidence interval (CI) 1.38-3.81] and receiving infertility treatments (OR 3.44,95%CI 1.76-6.73). Moreover, fecunditywasnotably affected because treated women had significantly reduced odds of achieving at least one live birth (OR 0.26, 95% CI 0.13-0.52). Remarkably, duration of treatment was correlated with time to pregnancy (r = 0.23, P = 0.008). Ovarian function was assessed in 174 tall women (119 treated, 55 untreated). Thirty-nine women (23%) exhibited a hypergonadotropic profile. After adjusting for age category, treated women had significantly higher odds of being diagnosed with imminent ovarian failure (OR 2.83, 95% CI 1.04-7.68). Serum FSH levels in these women were significantly increased, whereas antral follicle counts and serum anti-Müllerian hormone levels were decreased. Conclusion: High-dose estrogen-treated tall women are at risk of subfertility in later life. Their fecundity is significantly reduced. Treated women exhibit signs of accelerated ovarian aging with concomitant follicle pool depletion, which may be the basis of the observed subfertility. Copyright

Limited value of ovarian function markers following orthotopic transplantation of ovarian tissue after gonadotoxic treatment (Article)

2011-04-01T00:00:00Z

Context: In young women, some treatments for cancer or other conditions (such as sickle cell anemia) may give rise to primary ovarian insufficiency. Ovarian transplantation is one of the available options for fertility preservation, with highly variable pregnancy rates. Objective: The objective of the study was to investigate markers of ovarian reserve and ovarian function inwomenup to 7 yr after orthotopic ovarian transplantation. Secondary objectives were to assess the relationship between markers of ovarian reserve and pregnancy rate along with the duration of ovarian function. Design: This was a prospective cohort study in 10 women, with a mean follow-up of 2.5 yr. Setting: The study was conducted at a university hospital in Brussels, Belgium. Patients: Patients included 10 women who were about to receive or had previously received gonadotoxic treatment. In seven women cryopreservation of ovarian tissue was performed before starting treatment. Subsequently autografts were orthotopically transplanted in these women. Three women, who had already developed primary ovarian insufficiency due to treatment, underwent orthotopic transplantationofovarianallograft tissue originatingfromtheirhumanleukocyteantigen-compatible sisters. Main Outcome Measures: Serum concentrations of FSH, LH, estradiol, inhibin B, and anti-Müllerian hormone (AMH) were measured. Results: On average, first menses took place after 4.7 months. Duration of graft functioning varied from 2 to more than 60 months. FSH concentrations remained elevated, whereas estradiol levels normalized andAMHwas low to undetectable. Inhibin B varied among women and was not associated with the duration of ovarian function (hazard ratio 0.966, 95% confidence interval 0.881-1.059). Two spontaneous pregnancies occurred. Endocrine characteristics were not significantly different in these women. Conclusions: Low AMH and inhibin B concentrations may suggest decreased ovarian reserve in women after ovarian transplantation.AMHand inhibin B levels may not be associated with the duration of ovarian graft function or probability to achieve a pregnancy. Copyright

Oligoovulatory and anovulatory cycles in women with polycystic ovary syndrome (PCOS): What's the difference? (Article)

2010-12-01T00:00:00Z

Context: Polycystic ovary syndrome (PCOS) is a heterogeneous disorder. The phenotype may differ between patients who exhibit signs of recent ovulation and anovulatory PCOS patients. Objective: Our objective was to study differences in clinical and endocrine characteristics and response to ovulation induction (OI) treatment comparing oligoovulatory and anovulatory PCOS patients. Design and Setting: We conducted a retrospective cohort study at a tertiary hospital. Patients: PCOS patients (n = 1750) presenting with oligo- or amenorrhea were diagnosed according to the Rotterdam 2003 consensus criteria. Arbitrarily, oligoovulatory PCOS was defined by a single random serum progesterone level of 10 nmol/liter or higher. Main Outcome Measures: We evaluated the incidence of oligo- or amenorrhea, menstrual cycle length, serum androgen levels, follicle count, and OI outcome parameters. Results: Anovulatory women (n = 1541 of 1750, 88.1%) were more often amenorrheic (P < 0.001) and presented with a longer cycle duration (P<0.001) compared with oligoovulatory women (n= 209 of 1750, 11.9%). Serum levels of testosterone (P<0.001), the free androgen index (P<0.001), and total follicle count (P < 0.005) were higher in anovulatory compared with oligoovulatory patients. During clomiphene citrate OI, more oligoovulatory women gained regular menstrual cycles (P < 0.05), whereas after second-line treatment with recombinant FSH, more anovulatory women became pregnant (P < 0.05). Conclusions: Oligoovulatory women with PCOS exhibit a milder phenotype of ovarian dysfunction and have a more favorable response to OI treatment using clomiphene citrate compared with anovulatory PCOS patients. However, during second-line treatment with recombinant FSH, anovulatory PCOS patients presented with a higher chance of pregnancy compared with oligoovulatory patients. Copyright

Ovarian stimulation for in vitro fertilization alters the intrauterine cytokine, chemokine, and growth factor milieu encountered by the embryo (Article)

2010-10-01T00:00:00Z

Objective: To elucidate the impact of ovarian stimulation on the intrauterine milieu represented by the cytokine, chemokine, and growth factor profile in endometrial secretions aspirated before embryo transfer. Design: Prospective cohort study. Setting: Fertility center in tertiary referral university hospital. Patient(s): Forty-two patients undergoing ovarian stimulation with GnRH analogues were recruited. They participated in both a natural and an ovarian-stimulated cycle for within patient comparisons. Intervention(s): Endometrial secretion aspiration was performed immediately before embryo transfer. Main Outcome Measure(s): The concentrations of 17 mediators known to be involved in human embryo implantation were assessed by multiplex immunoassay. Result(s): After correction for multiple testing, significantly higher concentrations of interleukin (IL)-1β, IL-5, IL-10, IL-12, IL-17, tumor necrosis factor (TNF)-α, heparin-binding epidermal growth factor (HbEGF), eotaxin, and dickkopf homologue-1 were present in endometrial secretions obtained in stimulated compared with natural cycles. Conclusion(s): Endometrial secretion analysis provides a novel means of investigating the effect of ovarian stimulation on the intrauterine milieu. The in vivo milieu encountered by the embryo after transfer is significantly altered by ovarian stimulation. Copyright

The fate of the mosaic embryo: Chromosomal constitution and development of Day 4, 5 and 8 human embryos (Article)

2010-08-01T00:00:00Z

Background: Post-zygotic chromosome segregation errors are very common in human embryos after in vitro fertilization, resulting in mosaic embryos. However, the significance of mosaicism for the developmental potential of early embryos is unknown. We assessed chromosomal constitution and development of embryos from compaction to the peri-implantation stage. Methods: From 112 cryopreserved Day 4 human embryos donated for research, 21 were immediately fixed and all cells were analysed by fluorescent in situ hybridization (FISH) for chromosomes 1, 7, 13, 15, 16, 18, 21, 22, X and Y. The remaining 91 embryos were thawed, with 54 embryos undergoing biopsy of one or two cells which were fixed and analysed by FISH. Biopsied embryos were kept in standard culture conditions for 24 h. Embryos arrested before cavitation (n = 24) were fixed whereas developing Day 5 blastocysts (n = 24) were co-cultured for a further 72 h on an endometrial monolayer followed by fixation. Cell numbers were counted and all nuclei were analysed by FISH. Data from a previous FISH analysis on cryopreserved good-quality Day 5 blastocysts (n = 36) were also included in the present study. Results: FISH analysis was successful for 18 Day 4 fixed embryos and, according to our definition, 83 were mosaic and 11 showed a chaotic chromosomal constitution. FISH analysis of two blastomeres from Day 4 developing embryos showed that 54 were mosaic, 40 were normal and 6 were abnormal. Analysis of Day 4, 5 and 8 whole embryos showed a decrease in incidence of mosaicism over time, from 83 on Day 4 to 42 on Day 8. A significant positive correlation was observed between the total cell number and the percentage of normal cells in developing Day 5 and Day 8 embryos but not in developing Day 4 or embryos arrested before cavitation. Conclusions: These data suggest that both the developmental arrest of a significant proportion of mosaic embryos on Day 4, and the cell death or reduced proliferation of aneuploid cells within an embryo may be responsible for the observed decrease of aneuploid blastomeres from compaction to the peri-implantation stage.

Hypertensive pregnancy complications in poor and normal responders after in vitro fertilization (Article)

2010-01-15T00:00:00Z

Objective: To investigate whether women pregnant after a poor response in IVF have pregnancy-induced hypertension and preeclampsia more frequently than women with pregnancies after a normal response in IVF. Poor response to ovarian stimulation for IVF reflects advanced ovarian aging, which may be associated with early vascular aging. This may become apparent in an increased incidence of hypertensive pregnancy complications in pregnancies achieved after poor response in IVF. Design: Patient-control study. Setting: Tertiary Fertility Center. Patient(s): One hundred fifty poor (three oocytes or fewer) and 150 normal responders (8-12 oocytes) pregnant after IVF-intracytoplasmic sperm injection (ICSI), matched for age, type of infertility, dose of recombinant FSH, singleton or twin pregnancy, and IVF or ICSI treatment. Intervention(s): None. Main Outcome Measure(s): Primary end points were birth weight of the neonate and the incidence of pregnancy-related hypertensive disorders. Secondary end points were duration of pregnancy, type of delivery, and live birth of the neonate. Result(s): Poor and normal responders did not have significantly different incidences in pregnancy-related hypertensive disorders, nor did their neonates differ significantly in birth weight. Moreover, duration of pregnancy, type of delivery, and live birth ratios were similar in both poor and normal responders. Conclusion(s): From this matched control study we were unable to confirm our hypothesis, that women pregnant after a poor response in IVF have pregnancy-induced hypertension and preeclampsia more frequently than women with pregnancies after a normal response in IVF. These results do not support a vascular etiology of poor response.

Comparison of inter-and intra-cycle variability of anti-Müllerian hormone and antral follicle counts (Article)

2010-01-01T00:00:00Z

BACKGROUND: The antral follicle count (AFC) and anti-Müllerian hormone (AMH) both represent age-related follicular decline quite accurately, although long-term follow-up studies are still lacking. The best ovarian reserve test would need only a single, cycle-independent measurement to be representative. METHODS: To compare the inter-and intra-cycle stability of AFC and AMH, we used age-adjusted intra-class correlation coefficients (ICCs). To measure inter-cycle stability across a number of up to four menstrual cycles, we used data, prospectively collected for the purpose of an other study, from 77 regularly cycling, infertile women aged 24-40 years. AMH and AFC values were measured on cycle day 3. To study intra-cycle variability, we used data from a prospective cohort study of 44 regularly cycling volunteers, aged 25-46 years and measured AMH and assessed the AFC (2-10 mm) every 1-3 cycle days. RESULTS: Between menstrual cycles, AFC and AMH varied between 0 and 25 follicles (median 10), and 0.3 and 27.1 ng/ml (median 4.64). The difference in age-adjusted ICC between AMH [ICC, 0.89 (95% CI, 0.84-0.94)] and AFC [ICC, 0.71 (95% CI, 0.63-0.77)] was 0.18 (95% CI, 0.12-0.27). For the intra-cycle variation, 0-43 antral follicles (median 7) were counted per volunteer. The difference in age-adjusted ICC between AMH [ICC, 0.87 (95% CI, 0.82-0.91)] and AFC [ICC, 0.69 (95% CI, 0.46-0.82)] was 0.18 (95% CI, 0.034-0.42). CONCLUSION: SSerum AMH demonstrated less individual intra-and inter-cycle variation than AFCs and may therefore be considered a more reliable and robust means of assessing ovarian reserve in subfertile women.

Genome-wide association study in premature ovarian failure patients suggests ADAMTS19 as a possible candidate gene (Article)

2009-09-01T00:00:00Z

BACKGROUND: Spontaneous premature ovarian failure (POF) occurs in 1% of women and has major implications for their fertility and health. Besides X chromosomal aberrations and fragile X premutations, no common genetic risk factor has so far been discovered in POF. Using high-density single nucleotide polymorphism (SNP) arrays, we set out to identify new genetic variants involved in this condition. METHODS: A genome-wide association study involving 309 158 SNPs was performed in 99 unrelated idiopathic Caucasian POF patients and 235 unrelated Caucasian female controls. A replication study on the most significant finding was performed. We specifically focused on chromosomal areas and candidate genes previously implicated in POF. RESULTS: Suggestive genome-wide significant association was observed for rs246246 (allele frequency P = 6.0 × 10-7) which mapped to an intron of ADAMTS19, a gene known to be up-regulated in the female mouse gonads during sexual differentiation. However, replication in an independent Dutch cohort (60 POF patients and 90 controls) could not confirm a clear association (P = 4.1 × 10-5in a joint analysis). We did not observe strong evidence for any of 74 selected POF candidate genes or linkage regions being associated with idiopathic POF in Caucasian females, although suggestive association (P < 0.005) was observed for SNPs that mapped in BDNF, CXCL12, LHR, USP9X and TAF4B. CONCLUSION: We observed a possible association between POF and a SNP in a biologically plausible candidate gene. Although limited by sample size, this proof-of-principle study's findings reveal ADAMTS19 as a possible candidate gene for POF and thus a larger follow-up study is warranted.

Genetic polymorphisms of GnRH and gonadotrophic hormone receptors affect the phenotype of polycystic ovary syndrome (Article)

2009-08-01T00:00:00Z

BACKGROUNDPolycystic ovary syndrome (PCOS) is a complex genetic disorder. Multiple functional polymorphisms have been identified in genes that regulate the hypothalamic-pituitary-gonadal (HPG) axis that regulates ovarian function. The present study aims to examine the influence of genetic variants of the HPG-axis on the severity of clinical features of PCOS and disease susceptibility.METHODSWe included 518 Caucasian PCOS women and 2996 unselected controls from the general population (the Rotterdam study). Genotype distributions were compared between patients and controls. Subsequently, associations with clinical features of PCOS were studied. Single nucleotide polymorphisms were selected in GnRH (Trp16Ser [rs6185]), the FSH-receptor (FSHR, Ala307Thr [rs6165] and Asn680Ser [rs6166]) and the LH-receptor (18insLQ, Asn291Ser [rs12470652] and Ser312Asn [rs2293275]).RESULTSFSHR Ser680was associated with higher levels of gonadotrophic hormones (FSH: P < 0.01, LH: P = 0.01), and testosterone (P = 0.05) and a higher frequency of hyperandrogenism (P = 0.04). No differences in risk for PCOS in association with the FSH-receptor variants were observed.CONCLUSIONGenetic variants of the HPG-axis were associated with a modest but significant effect on the phenotype of PCOS. FSHR variants were strongly associated with the severity of clinical features of PCOS, such as levels of gonadotrophic hormones and the presence of hyperandrogenism, but not disease risk.

Endometrial secretion analysis identifies a cytokine profile predictive of pregnancy in IVF (Article)

2009-06-01T00:00:00Z

Background: The study of human endometrial-embryonic interactions is complicated by the disruptive impact of endometrial sample collection on the process of implantation itself. Endometrial secretion analysis is a novel technique, non-disruptive to implantation. The primary aim of this prospective cohort study was to explore whether a cytokine profile predictive of implantation and clinical pregnancy can be identified in endometrial secretions aspirated immediately prior to embryo transfer following IVF. Methods: Endometrial secretions, aspirated immediately prior to embryo transfer from 210 women undergoing IVF, were analyzed using a multiplex immunoassay for 17 soluble regulators of implantation, namely interleukin (IL)-1β, IL-5, IL-6, IL-10, IL-12, IL-15, IL-17, IL-18, tumor necrosis factor (TNF)-α, interferon (IFN)-γ, macrophage migration inhibitory factor, eotaxin, IFN-γ-inducible 10 kDa protein (IP-10), monocyte chemo-attractant protein-1 (MCP-1), Dickkopf homolog 1, heparin-binding epidermal growth factor and vascular endothelial growth factor (VEGF). In order to detect implantation, daily urine samples were collected after embryo transfer, and human Chorionic Gonadotropin (hCG) concentrations were analyzed by an immunoassay. Results: Multivariable logistic regression analysis revealed significant associations (negative and positive association, respectively) between MCP-1 (P = 0.005) and IP-10 (P = 0.037) levels and implantation, and between IL-1β (P = 0.047) and TNF-α (P = 0.023) levels and clinical pregnancy. The predictive value for pregnancy of IL-1β and TNF-α was observed to be equivalent and additive to that of embryo quality. Conclusions: Endometrial secretion cytokine profiling offers a novel, non-disruptive approach to study the role of the endometrium in human embryo implantation and identifies a profile which appears to be conducive to clinical pregnancy.

Anti-Müllerian hormone, inhibin b, and antral follicle count in young women with ovarian failure (Article)

2009-03-01T00:00:00Z

Context: Ovarian dysfunction is classically categorized on the basis of cycle history, FSH, and estradiol levels. Novel ovarian markers may provide a more direct insight into follicular quantity in hypergonadotropic women.Objective: The objective of the study was to investigate the distribution of novel ovarian markers in young hypergonadotropic women as compared with normogonadotropic regularly menstruating women.Design: This was a nationwide prospective cohort study.Setting: The study was conducted at 10 hospitals in The Netherlands.Patients: Women below age 40 yr with regular menses and normal FSH controls; n = 83), regular menstrual cycles and elevated FSH [incipient ovarian failure (IOF); n = 68]; oligomenorrhea and elevated FSH [referred to as transitional ovarian failure (TOF); n = 79]; or at least 4 months amenorrhea together with FSH levels exceeding 40 IU/liter [premature ovarian failure (POF); n = 112].Main Outcome Measures: Serum levels of anti-Mullerian hormone (AMH), inhibin B, and antral follicle count (AFC) was measured.Results: All POF patients showed AMH levels below the fifth percentile (p5) of normoovulatory women. Normal AMH levels (>p5) could be identified in 75% of IOF, 33% of TOF patients, and 98% of controls. AFC and AMH levels changed with increasing age (P <0.0001), whereas inhibin B did not [P = 0.26). AMH levels were significantly different between TOF and IOF over the entire age range, whereas AFC became similar for TOF and IOF at higher ages.Conclusions: Compared with inhibin B and AFC, AMH was more consistently correlated with the clinical degree of follicle pool depletion in young women presenting with elevated FSH levels. AMH may provide a more accurate assessment of the follicle pool in young hypergonadotropic patients, especially in the clinically challenging subgroups of patients with elevated FSH and regular menses (i.e. IOF) and in hypergonadotropic women with cycle disturbances not fulfilling the POF diagnostic criteria (i.e. TOF).

The clinical significance of the retrieval of a low number of oocytes following mild ovarian stimulation for IVF: A meta-analysis (Article)

2009-01-05T00:00:00Z

Background: Milder ovarian stimulation protocols for in vitro fertilization (IVF) are being developed to minimize adverse effects. Mild stimulation regimens result in a decreased number of oocytes at retrieval. After conventional ovarian stimulation for IVF, a low number of oocytes are believed to represent poor ovarian reserve resulting in reduced success rates. Recent studies suggest that a similar response following mild stimulation is associated with better outcomes. Methods: This review investigates whether the retrieval of a low number of oocytes following mild ovarian stimulation is associated with impaired implantation rates. Three randomized controlled trials comparing the efficacy of the mild ovarian stimulation regimen (involving midfollicular phase initiation of FSH and GnRH co-treatment) for IVF with a conventional long GnRH agonist co-treatment stimulation protocol could be identified by means of a systematic literature search. Results: These studies comprised a total of 592 first treatment cycles.Individual patient data analysis showed that the mild stimulation protocol results in a significant reduction of retrieved oocytes compared with conventional ovarian stimulation (median 6 versus 9, respectively, P < 0.001). Optimal embryo implantation rates were observed with 5 oocytes retrieved following mild stimulation (31%) versus 10 oocytes following conventional stimulation (29%) (P = 0.045). Conclusions: The optimal number of retrieved oocytes depends on the ovarian stimulation regimen. After mild ovarian stimulation, a modest number of oocytes is associated with optimal implantation rates and does not reflect a poor ovarian response. Therefore, the fear of reducing the number of oocytes retrieved following mild ovarian stimulation appears to be unjustified.

The feasibility of a less invasive method to assess endometrial maturation - Comparison of simultaneously obtained uterine secretion and tissue biopsy (Article)

2009-01-01T00:00:00Z

Objective: To compare the assessment of endometrial maturation parameters in endometrial secretion samples obtained by a novel minimally invasive technique with those assessed in tissue biopsies. Design: Prospective study. Setting: University Hospital. Population: Healthy female volunteers attending a gynaecological outpatient clinic. Methods: Endometrial secretion fluid and tissue sampling 5 days after a spontaneous ovulation assessed with ultrasound. Main outcome measures: Progesterone (P) receptor, Ki-67 expression and the Noyes criteria were used to date endometrial biopsies. In the endometrial fluid samples, glycodelin A (GdA), leukaemia inhibitory factor (LIF) and P levels were analysed, and protein content and electrophoresis patterns were determined. Results: All data were correlated to estradiol (E2) and P serum concentrations. The dating according to histology and immunohistochemical staining patterns correlated significantly with GdA levels (r = 0.376, P = 0.048) in endometrial fluid samples as well with serum levels of E2(r = 0.568, P = 0.001) and P (r = 0.408, P = 0.023). No correlation was observed between tissue dating and LIF levels and protein content in endometrial fluid samples. Conclusions: The measurement of GdA in endometrial secretion samples may provide a less invasive method for assessing endometrial maturation in potential conception cycles without disrupting implantation.

A randomized dose-response trial of a single injection of corifollitropin alfa to sustain multifollicular growth during controlled ovarian stimulation (Article)

2008-11-01T00:00:00Z

BACKGROUND: This study primarily investigated the dose-response relationship of corifollitropin alfa to initiate multifollicular development for the first 7 days of controlled ovarian stimulation (COS). METHODS: Women aged 20-39 years undergoing COS for in vitro fertilization or intracytoplasmic sperm injection were randomized to a single dose of corifollitropin alfa 60, 120 or 180 μg, or daily injections of 150 IU recombinant follicle-stimulating hormone (rFSH). Patients treated with corifollitropin alfa started fixed daily treatment with 150 IU rFSH on stimulation Day 8. Patients received a GnRH antagonist (ganirelix 0.25 mg/day) from stimulation Day 5 until the day of human chorionic gonadotrophin. RESULTS: Pharmacokinetics of corifollitropin alfa were dose-proportional. The main reason for not having embryo transfer was insufficient ovarian response in 30.8, 2.6, 3.8 and 7.4% of patients in the corifollitropin alfa 60, 120, 180 μg and rFSH groups, respectively. On Day 8, the mean (standard deviation) number of follicles ≥11 mm was 6.8 (4.4), 10.1 (6.1) and 12.8 (7.5), respectively. The number of cumulus-oocyte complexes retrieved showed a clear dose-response relationship (P < 0.0001), being 5.2 (5.5), 10.3 (6.3) and 12.5 (8.0) in the three dose groups, respectively. CONCLUSIONS: A single injection of corifollitropin alfa induces dose-related increase in multifollicular development and in the number of retrieved oocytes. The optimal dose for a 1-week interval is higher than 60 μg and lower than 180 μg and will be selected based on modelling and simulation taking into account insufficient stimulation as well as overstimulation. Clinical Trials gov: NCT00598208.

Anti-Müllerian hormone and ovarian dysfunction (Article)

2008-11-01T00:00:00Z

Anti-Müllerian hormone (AMH) has important roles in postnatal ovarian function. Produced by ovarian granulosa cells, AMH is involved in initial follicle development. In fact, serum AMH level correlates with ovarian follicle number. In patients with polycystic ovary syndrome (PCOS), AMH levels are elevated, which indicates its potential relevance in PCOS diagnosis and management. AMH represents a useful clinical marker for the assessment of ovarian reserve in cases of subfertility caused by advanced age in women. A potential role for AMH in dominant follicle selection has also been suggested. Future challenges comprise the availability of a well-standardized assay and the development of AMH agonists and antagonists as possible tools to manipulate ovarian function for contraception or ovarian longevity.

Why do couples drop-out from IVF treatment? A prospective cohort study (Article)

2008-09-01T00:00:00Z

BACKGROUND: Cumulative IVF pregnancy rates are compromised by the large number of couples who drop-out of treatment before achieving pregnancy. The aim of this study was to identify the role of the treatment strategy applied, and potential other factors that influence the decision of couples to discontinue treatment. METHODS: The incidence of drop-out from IVF treatment and factors related to drop-out were studied in a cohort of IVF patients aged <38 years embarking on IVF treatment either with a mild or a standard treatment strategy for a planned maximum number of treatment cycles. RESULTS: Of the 384 couples studied, 17% dropped out of IVF treatment. The physical or psychological burden of treatment was the most frequent cause of drop-out (28%). The application of a mild treatment strategy (mild ovarian stimulation along with the transfer of a single embryo) significantly reduced the chance of drop-out (hazard ratio (HR) 0.55; 95% confidence interval (CI), 0.31-0.96). When a mild IVF strategy was employed, the association between the baseline anxiety score and drop-out was reduced by >50%. The presence of severe male subfertility (HR 4.80; 95% CI, 1.63-14.13) and the failure to achieve embryo transfer (odds ratio 0.41; 95% CI, 0.24-0.72) were also related to drop-out. CONCLUSIONS: Reducing drop-out rate is crucial to further improve the efficacy and cost-effectiveness of IVF treatment. An important factor determining the risk of drop-out is the burden of the treatment strategy. The application of a mild treatment strategy and managing patient's expectations might reduce drop-out rates.

Lipid profile of women with premature ovarian failure (Article)

2008-09-01T00:00:00Z

OBJECTIVE: Earlier menopause is associated with a higher incidence of cardiovascular events later in life. Concurrent with the ages of menopausal transition, a shift in lipid profile takes place. Premature ovarian failure (POF) or premature menopause allows us to study the effect of cessation of ovarian function on the lipid profile independent of effects of advanced chronological age. DESIGN: Fasting triglycerides (TGs), total high-density lipoprotein (HDL), and low-density lipoprotein cholesterol levels were measured in 90 women with POF not using any hormone therapy and 198 population controls of the same age range not using oral contraceptives. Correlations between lipids and ovarian function parameters were assessed. RESULTS: After correction for age, body mass index, and smoking, women with POF presented with significantly higher TG levels (mean difference: 0.17 log mmol/L [95% CI: 0.06-0.29]). HDL cholesterol levels were borderline significantly lower in women with POF. No age-corrected correlation between triglycerides or other lipids and estradiol levels or time of estrogen deprivation could be identified. However, the free androgen index, sex hormone-binding globulin, and testosterone concentrations showed significant correlations with TGs and/or HDL cholesterol concentrations. CONCLUSIONS: Loss of ovarian function at a very young age (POF) coincides with subtle changes in the lipid profile (higher TG levels and marginally lower HDL). Androgens (increased free androgen index and testosterone and decreased sex hormone-binding globulin) are better markers for unfavorable lipid changes compared with estrogen levels or duration of estrogen deprivation in women with POF. Elevated TG levels in combination with increased (free) androgens may be an early manifestation of reduced insulin sensitivity.

Predictors of ongoing pregnancy after single-embryo transfer following mild ovarian stimulation for IVF (Article)

2008-05-01T00:00:00Z

Objective: To develop a prognostic model for the prediction of ongoing pregnancy after single-embryo transfer (SET) following mild stimulation for IVF in women less than 38 years of age. Design: Prospective cohort study. Setting: Two fertility centers in tertiary referral university hospitals. Patient(s): A total of 152 women with an elective SET following mild ovarian stimulation (cycle day 5 start of 150 IU/day recombinant FSH and late follicular phase GnRH antagonist cotreatment). Intervention(s): Database analysis. Main outcome measure(s): Ongoing pregnancy. Result(s): The ongoing pregnancy rate per elective SET was 28% (42 of 152). In a multivariate logistic regression analysis, body mass index, the total gonadotrophin dose needed, and number of oocytes retrieved were negatively correlated whereas the availability of a top-quality embryo was positively correlated with ongoing pregnancy. The predictive ability of the model assessed by the area under the receiver operating characteristic curve was 0.68. At a probability cut-off level of 0.20 the model showed a sensitivity of 37% and a specificity of 90%. Conclusion(s): The developed prediction model for ongoing pregnancy provides an evidence-based strategy for guidance under which conditions SET may be performed. After external validation, application of the model may help to improve overall singleton pregnancy rates.

The impact of ovarian stimulation with recombinant FSH in combination with GnRH antagonist on the endometrial transcriptome in the window of implantation (Article)

2008-05-01T00:00:00Z

The aim of this prospective paired cohort study is to elucidate the impact of ovarian stimulation with recombinant follicle-stimulating hormone in combination with gonadotropin-releasing hormone antagonist on the endometrial transcriptome. Oocyte donors underwent endometrial biopsy during the implantation window of the nonstimulated cycle and following ovarian stimulation with recombinant follicle-stimulating hormone and gonadotropin-releasing hormone antagonist but no luteal progesterone supplementation (n = 4). Microarray analysis showed 142 genes to be significantly upregulated and 98 significantly downregulated. Significantly upregulated genes included those sequencing for the chemokine ligand CXCL 13, the Dickkopf homolog, steroidogenic acute regulatory protein, and homeobox C6. Also upregulated were genes inhibited by progesterone, such as insulin-like growth factor binding protein 5. In conclusion, ovarian stimulation with follicle-stimulating hormone and gonadotropin-releasing hormone antagonist dysregulates the expression of many genes involved in cell adhesion, T-cell receptor signaling, and regulation of signal transduction. These data suggest that dysregulation of the endometrial transcriptome in the stimulated cycle is not fully attributable to supraphysiological sex steroid levels at the folliculo-luteal transition.

A more atherogenic serum lipoprotein profile is present in women with polycystic ovary syndrome: A case-control study (Article)

2008-02-01T00:00:00Z

Context: Polycystic ovary syndrome (PCOS) is associated with a higher frequency of cardiovascular risk factors. Apolipoprotein (apo) A-I and apoB are potent markers for cardiovascular risk. Data on apo levels in women with PCOS are scarce and contradictory. Objective: Our objective was to identify changes in lipid metabolism in women with PCOS, and the relative impact of obesity, insulin resistance, and hyperandrogenism on lipid parameters. Design: This was a case-control study. Setting: The study was performed at a single referral center. Subjects: PCOS was diagnosed according to the 2003 Rotterdam criteria. Healthy mothers with regular menstrual cycles served as controls. Main Outcome Parameters: Fasting insulin, triglycerides (TGs), cholesterol, high-density lipoprotein (HDL)-cholesterol, apoA-I, and apoB were determined. Low-density lipoprotein (LDL)-cholesterol was calculated using the Friedewald formula. Results: We included 557 women with PCOS and 295 controls. After correction for age and body mass index, PCOS women had higher median levels of insulin (10.1 vs. 6.9 mU/liter), TGs (95 vs. 81 mg/dl), cholesterol (196 vs. 178 mg/dl), and LDL-cholesterol (125 vs. 106 mg/dl) in combination with lower levels of HDL-cholesterol (46 vs. 55 mg/dl) and apoA-I (118 vs. 146 mg/dl) compared with controls (all P values ≤ 0.01). apoB levels were similar in cases and controls. Free androgen index, body mass index, SHBG, and estradiol were independent predictors of apoA-I levels inwomenwith PCOS. Conclusions: PCOS is associated with a more pronounced atherogenic lipid profile. Furthermore, obesity and hyperandrogenism contribute to an adverse lipid profile. Finally, PCOS seems to constitute an additional risk factor for an atherogenic lipid profile. Copyright

Cost-effectiveness of a mild compared with a standard strategy for IVF: A randomized comparison using cumulative term live birth as the primary endpoint (Article)

2008-02-01T00:00:00Z

BACKGROUND: Conventional ovarian stimulation and the transfer of two embryos in IVF exhibits an inherent high probability of multiple pregnancies, resulting in high costs. We evaluated the cost-effectiveness of a mild compared with a conventional strategy for IVF. METHODS: Four hundred and four patients were randomly assigned to undergo either mild ovarian stimulation/GnRH antagonist co-treatment combined with single embryo transfer, or standard stimulation/GnRH agonist long protocol and the transfer of two embryos. The main outcome measures are total costs of treatment within a 12 months period after randomization, and the relationship between total costs and proportion of cumulative pregnancies resulting in term live birth within 1 year of randomization. RESULTS: Despite a significantly increased average number of IVF cycles (2.3 versus 1.7; P < 0.001), lower average total costs over a 12-month period (8333 versus €10 745; P = 0.006) were observed using the mild strategy. This was mainly due to higher costs of the obstetric and post-natal period for the standard strategy, related to multiple pregnancies. The costs per pregnancy leading to term live birth were €19 156 in the mild strategy and €24 038 in the standard. The incremental cost-effectiveness ratio of the standard strategy compared with the mild strategy was €185 000 per extra pregnancy leading to term live birth. CONCLUSIONS: Despite an increased mean number of IVF cycles within 1 year, from an economic perspective, the mild treatment strategy is more advantageous per term live birth. It is unlikely, over a wide range of society's willingness-to-pay, that the standard treatment strategy is cost-effective, compared with the mild strategy.

Low negative affect prior to treatment is associated with a decreased chance of live birth from a first IVF cycle (Article)

2008-01-01T00:00:00Z

BACKGROUND: Psychological variables, such as anxiety and depression, may have a negative impact on IVF outcomes, but the evidence remains inconclusive. Previous studies have usually measured a single psychological parameter with clinical pregnancy as the outcome. The objective of the current study was to determine whether pretreatment or procedural psychological variables in women undergoing a first IVF cycle affect the chance of achieving a live birth from that cycle. METHODS: Between February 2002 and February 2004, 391 women with an indication for IVF were recruited at two University Medical Centres in The Netherlands. Pretreatment anxiety and depression were measured with the Hospital Anxiety and Depression Scale. The Daily Record Keeping Chart was used to measure negative and positive affect before treatment and daily during ovarian stimulation. Multiple stepwise forward logistic regression analysis was performed with term live birth as the dependent variable. RESULTS: Regression analysis showed that women who expressed less negative affect at baseline were less likely to achieve live birth (P = 0.03). After one IVF cycle, women who received a standard IVF strategy were more likely to reach live birth delivery than those who received a mild IVF strategy (P = 0.002). A male/female indication for IVF was associated with a higher chance of achieving term live birth than a female only indication (P = 0.03). Age, duration of infertility or type of infertility were not independent predictors of live birth. CONCLUSIONS: The relationship between psychological parameters and IVF success rates is more complex than commonly believed. The expression of negative emotions before starting IVF might not be always detrimental for outcomes.

Heterozygosity for the classical galactosemia mutation does not affect ovarian reserve and menopausal age (Article)

2007-12-01T00:00:00Z

Female patients with classical galactosemia (galactose-1-phosphate uridyltransferase [GALT] deficiency) frequently suffer from premature ovarian failure, despite treatment with a galactose-restricted diet. Earlier research has suggested an association between heterozygosity for GALT mutations and early menopause. This study evaluates the effect of carriership for classical galactosemia on ovarian reserve and menopausal age. Proven female carriers of classical galactosemia were recruited via the Dutch Galactosemia Society. All 58 participants underwent a structured interview regarding fertility, smoking status, and menopause. To determine ovarian reserve, 42 premenopausal GALT carriers underwent ovarian antral follicle count (AFC) by transvaginal ultrasound and early follicular phase blood sampling for hormonal measurement of follicle-stimulating hormone (FSH), inhibin B, and anti-Müllerian hormone (AMH). These ovarian reserve parameters were compared with a cohort of proven fertile women (n = 166). The mean age at menopause in GALT carriers was 49.7 years, which is not different from the mean age at menopause in the general population in the Netherlands. There was no difference in FSH, inhibin B, and AMH levels or in the AFC (when corrected for age and smoking status) between 42 premenopausal GALT carriers and controls. The authors conclude that there is no evidence that GALT mutation carriership affects ovarian reserve or menopausal age.

The psychological impact of IVF failure after two or more cycles of IVF with a mild versus standard treatment strategy (Article)

2007-09-01T00:00:00Z

Background: Failure of IVF treatment after a number of cycles can be devastating for couples. Although mild IVF strategies reduce the psychological burden of treatment, failure may cause feelings of regret that a more aggressive approach, including the transfer of two embryos, was not employed. In this study, the impact of treatment failure after two or more cycles on stress was studied, following treatment with a mild versus a standard treatment strategy. Methods: Randomized controlled two-centre trial (ISRCTN35766970). Women were randomized to undergo mild ovarian stimulation (including GnRH antagonist co-treatment) and single embryo transfer (n = 197) or standard GnRH agonist long-protocol ovarian stimulation with double embryo transfer (n = 194). Participants completed the Hospital Anxiety and Depression Scale prior to commencing treatment and 1 week after the outcome of their final treatment cycle was known. Data from women who underwent two or more IVF cycles were subject to analysis (n = 253). Results: Women who experienced treatment failure after standard IVF treatment presented more symptoms of depression 1 week after treatment termination compared with women who had undergone mild IVF: adjusted mean (±95% confidence interval) = 10.2 (±2.3) versus 5.4 (±1.8), respectively, P = 0.01. Conclusions: Failure of IVF treatment after a mild treatment strategy may result in fewer short-term symptoms of depression as compared to failure after a standard treatment strategy. These findings may further encourage the application of mild IVF treatment strategies in clinical practice.

Predictors of low response to mild ovarian stimulation initiated on cycle day 5 for IVF (Article)

2007-07-01T00:00:00Z

Background: Milder stimulation protocols are being developed to minimize adverse effects of ovarian stimulation in in vitro fertilization (IVF) programs. A drawback is the possibility of an increased rate of insufficient ovarian response. This study aimed to develop a prognostic model for the prediction of cycle cancellation due to insufficient response to mild stimulation. Methods: A total of 174 IVF patients aged <38 years and with a body mass index (BMI) <28 Kg/m2were treated with mild ovarian stimulation using a fixed daily dose (150 IU) of recombinant follicle-stimulating hormone (rFSH) from cycle day 5 and GnRH antagonist from the late follicular phase. In women with mono- or bifollicular growth (17%), the cycle was cancelled and the treatment was adjusted in a second treatment cycle by starting rFSH on cycle day. Results: In a multivariable logistic regression analysis, duration of infertility, menstrual cycle length, secondary infertility and BMI were included in the prediction model. The area under the receiver-operating characteristics curve of the model was 0.69. A probability cut-off for cancellation of 0.3 yielded an expected sensitivity of 33% and specificity of 92%. Analysis of ovarian response in the subsequent treatment cycle showed an improved ovarian response and a significant reduction in the cancellation rate. Conclusions: With the presented model, it is possible to identify patients at risk for cycle cancellation, during mild ovarian stimulation, due to insufficient response. The contributing factors of the model suggest that ovarian aging and BMI are related to insufficient response to mild stimulation.

Predictors of recovery of ovarian function during weight gain in anorexia nervosa (Article)

2007-04-01T00:00:00Z

Objective: To investigate whether serum levels of follicle-stimulating hormone (FSH), inhibin B, and anti-Müllerian hormone (AMH) can be used as predictors of recovery of ovarian function in anorexia nervosa after weight gain. Design: Follow-up cohort study. Setting: Two specialized treatment centers for eating disorders, one for adolescents (aged between 12 and 17 years) and one for adults (older than the age of 17 years). Patient(s): Sixty-one young women (mean age, 18.2 years) with anorexia nervosa. Intervention(s): None (standard treatment program). Main Outcome Measure(s): Time to recovery of menses. Result(s): Forty-two (69%) patients recovered in weight within the 1st year, of which only 24 (39%) reached resumption of regular menstrual cycles. Next to weight gain itself, initial ovarian endocrine markers such as FSH, inhibin B, and AMH hormone were capable of predicting chances for resumption of menses in a multivariate analysis with time to recovery as the main outcome measure. Conclusion(s): Initial ovarian endocrine markers FSH, inhibin B, and AMH can predict successful recovery of ovarian function in anorexia nervosa patients undergoing treatment to gain weight.

Milder ovarian stimulation for in-vitro fertilization reduces aneuploidy in the human preimplantation embryo: A randomized controlled trial (Article)

2007-04-01T00:00:00Z

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.

A mild treatment strategy for in-vitro fertilisation: a randomised non-inferiority trial (Article)

2007-03-03T00:00:00Z

Background: Mild in-vitro fertilisation (IVF) treatment might lessen both patients' discomfort and multiple births, with their associated risks. We aimed to test the hypothesis that mild IVF treatment can achieve the same chance of a pregnancy resulting in term livebirth within 1 year compared with standard treatment, and can also reduce patients' discomfort, multiple pregnancies, and costs. Methods: We did a randomised, non-inferiority effectiveness trial. 404 patients were randomly assigned to undergo either mild treatment (mild ovarian stimulation with gonadotropin-releasing hormone [GnRH] antagonist co-treatment combined with single embryo transfer) or a standard treatment (stimulation with a GnRH agonist long-protocol and transfer of two embryos). Primary endpoints were proportion of cumulative pregnancies leading to term livebirth within 1 year after randomisation (with a non-inferiority threshold of -12·5%), total costs per couple up to 6 weeks after expected date of delivery, and overall discomfort for patients. Analysis was by intention to treat. This trial is registered as an International Standard Randomised Clinical Trial, number ISRCTN35766970. Findings: The proportions of cumulative pregnancies that resulted in term livebirth after 1 year were 43·4% with mild treatment and 44·7% with standard treatment (absolute number of patients=86 for both groups). The lower limit of the one-sided 95% CI was -9·8%. The proportion of couples with multiple pregnancy outcomes was 0·5% with mild IVF treatment versus 13·1% (p<0·0001) with standard treatment, and mean total costs were €8333 and €10745, respectively (difference €2412, 95% CI 703-4131). There were no significant differences between the groups in the anxiety, depression, physical discomfort, or sleep quality of the mother. Interpretation: Over 1 year of treatment, cumulative rates of term livebirths and patients' discomfort are much the same for mild ovarian stimulation with single embryos transferred and for standard stimulation with two embryos transferred. However, a mild IVF treatment protocol can substantially reduce multiple pregnancy rates and overall costs.

FISH analysis of 15 chromosomes in human day 4 and 5 preimplantation embryos: The added value of extended aneuploidy detection (Article)

2007-01-01T00:00:00Z

Objective: Screening for an increased number of chromosomes may improve the detection of abnormal embryos and thus contribute to the capability of preimplantation genetic screening (PGS) to detect the embryo(s) for transfer in IVF with the best chance for a healthy child. Good-quality day 4 and 5 embryos were analyzed after cryopreservation for the nine chromosomes mostly recommended for screening (13, 14, 15, 16, 18, 21, 22, X and Y), next to six additional chromosomes which are less well studied in this context (1, 2, 7, 6, 10 and 17). Method: The copy numbers of 15 chromosomes were investigated by fluorescence in situ hybridization (FISH) in three consecutive rounds. The proportion of aneuploid and mosaic embryos was determined and compared in retrospect to results in case only the recommended probe set had been analyzed. Results: A total of 52 embryos from 29 infertile women were analyzed. Screening the embryos for six additional chromosomes increased the proportion of abnormal embryos from 67 to 81% (P = 0.03), owing to an increase in mosaic embryos. Conclusion: All but one of the meiotic aneuploidies found in this study would have been detected by the probe set most frequently used in PGS clinics. However, aneuploid cell lines originating from mitotic errors could be detected for almost all chromosomes, so screening of six additional chromosomes mainly increased the proportion of mosaic embryos. The added value of screening for six additional chromosomes in PGS for clinical practice will remain undetermined as long as the fate of mosaic embryos after transfer is unclear. Copyright

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

2005-04-01T00:00:00Z

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.

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

2005-03-01T00:00:00Z

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.

Changes in anti-Mullerian hormone serum concentrations over time suggest delayed ovarian ageing in normogonadotrophic anovulatory infertility. (Article)

2004-09-01T00:00:00Z

BACKGROUND: Anti-Mullerian 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.

What is the most relevant standard of success in assisted reproduction? The next step to improving outcomes of IVF: consider the whole treatment. (Article)

2004-09-01T00:00:00Z

Changing the way in which successful IVF treatment is defined offers a tool to improve efficacy while reducing costs and complications of treatment. Crucial to this paradigm shift is the move away from considering outcomes in terms of the single IVF cycle, and towards the started IVF treatment as a whole. We propose the most informative end-point of success in IVF to be the term singleton birth rate per started IVF treatment (or per given time period) in the overall context of patient discomfort, complications and costs. These end-points are important not only for patients, but also for clinicians, health economists and policy makers. Such an approach would encourage the development of patient-friendly and cheaper stimulation protocols with less stress, discomfort and side effects. The combination of mild ovarian stimulation with single embryo transfer may provide the same overall pregnancy rate per total IVF treatment, achieved in the same amount of time for similar direct costs, but with reduced patient stress and discomfort, and the near complete elimination of multiple pregnancies. This would offer major health and indirect cost benefits. If IVF success rates were to be expressed in terms of delivery of a term single baby per IVF treatment (or in a given treatment period), the introduction of single embryo transfer on a large scale would be facilitated.

Fluorescence in situ hybridization analysis of two blastomeres from day 3 frozen-thawed embryos followed by analysis of the remaining embryo on day 5. (Article)

2004-03-01T00:00:00Z

BACKGROUND: Chromosomal mosaicism in human embryos may give rise to false positive or false negative results in preimplantation genetic diagnosis for aneuploidy screening (PGD-AS). Therefore, we have investigated whether the results obtained from a 2-cell biopsy of frozen-thawed embryos and fluorescence in situ hybridization (FISH) analysis are representative for the chromosome constitution of the remaining embryo on day 5. METHODS: Cryopreserved day 3 embryos were thawed and from surviving embryos two blastomeres were biopsied. FISH analysis was performed for chromosomes 1, 7, 13, 15, 16, 18, 21, 22, X and Y. After biopsy, the embryos were cultured until day 5 and further analysed using the same probe panels. RESULTS: In all, 17 embryos were available with a diagnosis based on two blastomeres on day 3 and confirmatory studies on day 5. In 10 of these 17 cases the initial diagnosis could be confirmed. However, in only six cases cytogenetic results were concordant. Besides the 10 cases with a 'correct' diagnosis, there were six false positive results and one false negative, all involving mosaicism. CONCLUSIONS: Investigating the chromosomal constitution of two blastomere nuclei offers a good opportunity to study the incidence of chromosomal mosaicism in early embryo development. The confirmation rate of the results obtained on day 3 depends on the interpretation and is higher when considered from a clinical than from a cytogenetic point of view.

Anti-Mullerian hormone serum concentrations in normoovulatory and anovulatory women of reproductive age (Article)

2004-01-01T00:00:00Z

Anti-Mullerian hormone (AMH) concentrations correlate with the number of antral follicles as well as age and constitute an endocrine marker for ovarian aging. In normogonadotropic anovulatory infertile women [World Health Organization (WHO) class 2], the number of early antral follicles is usually increased. To investigate whether AMH concentrations are increased, serum levels in 128 WHO 2 women were compared with those in 41 normoovulatory premenopausal women of similar age. Serum AMH concentrations are significantly (P < 0.001) elevated in WHO 2 patients [median, 7.6 micro g/liter (range, 0.1-40.0)], compared with controls [median, 2.1 micro g/liter (0.1-7.4)]. In 106 patients presenting with polycystic ovaries (PCOs) (>/==" BORDER="0">12 follicles/ovary measuring 2-9 mm and/or an ovarian volume > 10 ml), AMH levels were elevated [9.3 micro g/liter (1.8-40.0)], compared with 22 patients without PCOs [6.4 micro g/liter (0.1-22.1)] (P < 0.0001). In WHO 2 patients, AMH concentrations correlated with features characteristic for polycystic ovary syndrome such as LH concentrations (r = 0.331; P = 0.0001), testosterone levels (r = 0.477, P = 0.0001), mean ovarian volume (r = 0.421; P = 0.0001), and the number of ovarian follicles (r = 0.308; P = 0.0001). AMH levels correlated well with age in WHO 2 patients (r = -0.248; P = 0.002) as well as in controls (r = -0.465; P = 0.005). However, the relative decline in AMH with age is less pronounced in WHO 2 patients. In a subset of patients no significant correlation was found between AMH serum concentrations and the FSH response dose, the duration of stimulation, and the total number of ampoules of FSH used. In conclusion, serum AMH concentrations are elevated in WHO 2 women, especially in those patients exhibiting PCOs. Because AMH concentrations correlated well with other clinical, endocrine, and ultrasound markers associated with polycystic ovary syndrome, AMH may be used as a marker for the extent of the disease. A less pronounced AMH decrease over time in these women may suggest retarded ovarian aging. The latter hypothesis, however, should be confirmed by longitudinal studies.

Management of infertility in a patient presenting with ovarian dysfunction and McCune-Albright syndrome (Article)

2004-01-01T00:00:00Z

Persistent autonomous ovarian dysfunction in McCune-Albright syndrome (MAS) patients is associated with the development of multiple dominant follicles, premature luteinization, cyst formation, and anovulatory infertility. Due to the mosaic distribution of the mutation, ovaries may be unequally affected. In the current patient, the least affected ovary became quiescent upon GnRH agonist-induced gonadotropin suppression. Normoovulatory cycles were restored after subsequent removal of the affected right ovary, and a pregnancy was established within 3 months. A healthy unaffected girl was born at term after an uneventful pregnancy. The placental tissue was normal, and the mutation was not detected in the placenta, umbilical cord structures, or umbilical cord blood. GnRH analog administration may help to identify those MAS patients who might benefit from unilateral ovariectomy. Because a healthy baby was born, evidence is provided suggesting that MAS is not passed on to the children from the parents.

A randomized comparison of two ovarian stimulation protocols with gonadotropin-releasing hormone (GnRH) antagonist cotreatment for in vitro fertilization commencing recombinant follicle-stimulating hormone on cycle day 2 or 5 with the standard long GnRH agonist protocol (Article)

2003-01-01T00:00:00Z

Extending the FSH window for multifollicular development by administering FSH from the midfollicular phase onward constitutes a novel mild protocol for ovarian stimulation for in vitro fertilization (IVF) based on the physiology of single dominant follicle selection in normo-ovulatory women. We compared outcomes from this protocol with two other stimulation protocols. One hundred and forty-two normo-ovulatory patients with an indication for IVF (or IVF/ICSI) were randomized to a GnRH agonist long protocol (group A; n = 45) or one of two GnRH antagonist protocols commencing recombinant FSH on cycle d 2 (group B; n = 48) or cycle d 5 (group C; n = 49). A fixed dose (150 IU/d) of rFSH was used for ovarian stimulation, and GnRH antagonist cotreatment was initiated on the day when the leading follicle reached 14 mm diameter. Group C showed a shorter duration of stimulation (median duration, 11, 9, and 8 d for groups A, B, and C, respectively; P < 0.001), reflected in a significantly lower total dose of rFSH used (median amount of rFSH, 1650, 1350, and 1200 IU for groups A, B, and C, respectively; P < 0.001). In group C more cycles were cancelled during the stimulation phase due to insufficient response, resulting in a lower percentage of oocyte retrievals (84%, 73%, and 63% for groups A, B, and C; P = 0.02). However, women in group C obtained better quality embryos (percentage of embryo score of 1 for best embryo, 29%, 37%, and 61% for groups A, B, and C, respectively; P = 0.008), resulting in more transfers per oocyte retrieval (68%, 71%, and 90% for groups A, B, and C, respectively; P = 0.04). After profound ovarian stimulation (groups A and B) only 7% of the patients who retrieved four oocytes or less conceived, whereas after mild stimulation (group C) 67% of these patients conceived (P < 0.01). Overall, no differences were found among the three groups comparing pregnancy rate per started IVF cycle. In conclusion, application of the described mild ovarian stimulation protocol resulted in pregnancy rates per started IVF cycle similar to those observed after profound stimulation with GnRH agonist cotreatment despite shorter stimulation and a 27% reduction in exogenous FSH. A higher cancellation rate before oocyte retrieval was compensated by improved embryo quality concomitant with a higher chance of undergoing embryo transfer. A relatively low number of oocytes retrieved after mild ovarian stimulation distinctly differs from the pathological reduction in the number of oocytes retrieved after profound ovarian stimulation (poor response) associated with poor IVF outcome. The relatively small number of oocytes obtained after mild ovarian stimulation may represent the best of the cohort in a given cycle.

Nonsupplemented luteal phase characteristics after the administration of recombinant human chorionic gonadotropin, recombinant luteinizing hormone, or gonadotropin-releasing hormone (GnRH) agonist to induce final oocyte maturation in in vitro fertilization patients after ovarian stimulation with recombinant follicle-stimulating hormone and GnRH antagonist cotreatment (Article)

2003-01-01T00:00:00Z

Replacing GnRH agonist cotreatment for the prevention of a premature rise in LH during ovarian stimulation for in vitro fertilization (IVF) by the late follicular phase administration of GnRH antagonist may render supplementation of the luteal phase redundant, because of the known rapid recovery of pituitary function after antagonist cessation. This randomized two-center study was performed to compare nonsupplemented luteal phase characteristics after three different strategies for inducing final oocyte maturation. Forty patients underwent ovarian stimulation using recombinant (r-)FSH (150 IU/d, fixed) combined with a GnRH antagonist (antide; 1 mg/d) during the late follicular phase. When at least one follicle above 18 mm was observed, patients were randomized to induce oocyte maturation by a single injection of either r-human (h)CG (250 microg) (n = 11), r-LH (1 mg) (n = 13), or GnRH agonist (triptorelin; 0.2 mg) (n = 15). Retrieved oocytes were fertilized by either IVF or intracytoplasmatic sperm injection, depending on sperm quality. Embryo transfer was performed 3-4 d after oocyte retrieval. No luteal support was provided. Serum concentrations of FSH, LH, estradiol (E(2)), progesterone (P), and hCG were assessed at fixed intervals during the follicular and luteal phase. The median duration of the luteal phase was 13, 10, and 9 d for the r-hCG, the r-LH, and the GnRH agonist group, respectively (P = 0.005). The median area under the curve per day (from 4 d post randomization until the onset of menses) for LH was 0.50, 2.34, and 1.07 for the r-hCG, the r-LH, and the GnRH agonist group, respectively (P = 0.001). The median area under the curve per day for P was 269 vs. 41 and 16 for the r-hCG, the r-LH, and the GnRH agonist group, respectively (P < 0.001). Low pregnancy rates (overall, 7.5%; range, 0-18% per started cycle) were observed in all groups. In conclusion, the nonsupplemented luteal phase was insufficient in all three groups. In the patients receiving r-hCG, the luteal phase was less disturbed, compared with both other groups, presumably because of prolonged clearance of hCG from the circulation and the resulting extended support of the corpus luteum. Despite high P and E(2) concentrations during the early luteal phase in all three groups, luteolysis started prematurely, presumably because of excessive negative steroid feedback resulting in suppressed pituitary LH release. Hence, support of corpus luteum function remains mandatory after ovarian stimulation for IVF with GnRH antagonist cotreatment.

High singleton live birth rate following classical ovulation induction in normogonadotrophic anovulatory infertility (WHO 2) (Article)

2003-01-01T00:00:00Z

BACKGROUND: Medical induction of ovulation using clomiphene citrate (CC) as first line and exogenous gonadotrophins as second line forms the classical treatment algorithm in normogonadotrophic anovulatory infertility. Because the chances of success following classical ovulation induction are not well established, a shift in first-line therapy can be observed towards alternative treatment. The study aim was to: (i) reliably assess the probability of singleton live birth following classical induction of ovulation; and (ii) construct a prediction model, based on individual patient characteristics assessed upon standardized initial screening, to help identify patients with poor chances of success. METHODS: A total of 240 consecutive women visiting a specialist academic fertility unit with a history of infertility, oligomenorrhoea or amenorrhoea, and normal FSH and estradiol serum concentrations (WHO group 2) was prospectively followed. The women had not been previously treated with ovulation-inducing agents. All patients commenced with CC. Patients who did not ovulate within three treatment cycles of incremental daily doses up to 150 mg for 5 consecutive days or ovulatory CC patients who did not conceive within six cycles, subsequently underwent gonadotrophin induction of ovulation applying a step-down dose regimen. The main outcome measure was pregnancy resulting in singleton live birth. Cox regression was used to construct a multivariable prediction model. RESULTS: Overall, there were 134 pregnancies ending in a singleton live birth (56% of women). The cumulative pregnancy rate after 12 and 24 months of follow-up was 50% and 71% respectively. Polycystic ovary syndrome (PCOS) patients (49%), clearly non-PCOS patients (13%) and the in-between group did not differ in prognosis (P = 0.9). The multivariable Cox regression model contained the woman's age, the insulin:glucose ratio and duration of infertility. With a cut-off value of 30% for low chance, the model predicted probabilities at 12 months lower than this cut-off for 25 out of 240 patients (10.4%). CONCLUSIONS: Classical ovulation induction produces very good results in normogonadotrophic anovulatory infertility. Alternative treatment options may not be indicated as first-line therapy in these patients, except for subgroups with poor prognosis. These women can be identified by older age, longer duration of infertility and higher insulin:glucose ratio.

Patient predictors for outcome of gonadotrophin ovulation induction in women with normogonadotrophic anovulatory infertility: a meta-analysis (Article)

2003-01-01T00:00:00Z

A systematic review was conducted to determine whether initial screening characteristics of women with normogonadotrophic anovulatory infertility predict clinically significant outcomes of ovulation induction with gonadotrophins, and to obtain pooled estimates of their predictive value through meta-analysis. Only those studies in which pre-treatment screening characteristics (such as body mass index, serum LH and androgens, insulin sensitivity and ultrasound appearance of ovaries) were related to outcome parameters (such as total amount of FSH administered, cancellation, ovulation, pregnancy and miscarriage), were included in this analysis. Thirteen studies fulfilled the inclusion criteria. A positive association was seen in all studies between the level of obesity (definition applied as assessed by individual studies) and total amount of FSH administered [weighted mean difference (WMD) of 771 IU (95% confidence interval (CI): 700-842)]. Pooled odds ratios (OR) of 1.86 (95% CI: 1.13-3.06) and 0.44 (95% CI: 0.31-0.61) were found between obesity with cancellation and ovulation respectively. Pooled analysis did not show a significant association between obesity and pregnancy rate. The pooled OR for obese versus non-obese women and miscarriage rate was significant [3.05 (95% CI: 1.45-6.44)]. Association measures between insulin resistance (definition applied as assessed by individual studies) and total amount of FSH administered produced a WMD of 351 (95% CI: 73-630) IU. A pooled OR of 0.29 (95% CI: 0.10-0.80) was found for insulin resistance with pregnancy rate. The pooled OR for insulin resistance (hyperinsuliaemia versus normoinsuliaemia) and miscarriage rate was not significant. A pooled OR of 1.04 (95% CI: 1.01-1.07) was found for LH (IU/l) with pregnancy rate. The pooled OR for LH and miscarriage rate was not significant. Finally, pooled analysis did not find a significant association between testosterone and pregnancy rate. In conclusion, the best available evidence, though limited, suggests that the most clinically useful predictors of gonadotrophin ovulation induction outcome in normogonadotrophic women are obesity and insulin resistance.

Is there a future for ovulation induction in the current era of assisted reproduction? (Article)

2003-01-01T00:00:00Z

The clinical use of medical induction of ovulation in normogonadotrophic anovulatory women (WHO II), including polycystic ovary syndrome, is increasingly questioned. However, we believe that this treatment modality still represents a highly effective means of fertility treatment in women with low pregnancy chances without intervention. A conventional treatment algorithm involving clomiphene citrate (CC) followed by FSH induction of ovulation may result in a 71% cumulative singleton live birth rate. In attempts to improve treatment outcome further and reduce complication rates, new compounds such as insulin-sensitizing agents or aromatase inhibitors are currently used increasingly. Approaches such as patient selection for different treatment modalities on the basis of initial screening characteristics and alternative protocols for FSH ovulation induction may also be proposed to render treatment algorithms more patient tailored and therefore improve overall outcomes. More research is needed in this area, rather than referring these patients to assisted reproduction prematurely. This may lead to a more individually tailored approach for ovulation induction in a given patient, resulting in a further improvement of the balance between chances for success versus complications.

Alternative approaches in IVF (Article)

2002-02-26T00:00:00Z

Various new developments in clinical and basic science which may impact on IVF in the near or distant future will be discussed in this review. These key areas include the regulation of early follicle development and the extended in vitro culture of oocytes and embryos. Moreover, alternative compounds and ovarian stimulation protocols will be discussed, along with highlights in the development of the cryopreservation of excess oocytes or embryos. Finally, the health economics of IVF is addressed.

Child development and quality of parenting in lesbian families: no psychosocial indications for a-priori withholding of infertility treatment. A systematic review (Article)

2002-01-01T00:00:00Z

Among fertility centres, much discussion focuses on whether to withhold infertility treatment from special patient groups (lesbians, prospective single parent(s), prospective parent(s) of relatively advanced age, or with severe diseases) because it is assumed that this is in the best interest of the child. The present study aimed to establish whether there is any empirical evidence for this assumption. A literature search was made in PubMed/Medline and PsycINFO to identify studies that had assessed psychological outcomes of children and quality of parenting after infertility treatment. Eight studies met the following inclusion criteria: published in an English-language peer-reviewed journal between 1978 and 2002, and focused on psychosocial child development and quality of parenting after infertility treatment in the above-mentioned special patient groups. All reviewed studies focused on lesbian or single-parent families. Overall, the methodological quality of studies as assessed by a standardized set of criteria was high. The evidence of the studies (assessed by the best evidence synthesis method) was strong for the conclusion that in lesbian families the psychosocial development of children (median age 6.1 years) and the quality of parenting are not different from those in healthy heterosexual two-parent families after infertility treatment or natural conception. Therefore, withholding infertility treatment from lesbian families on the assumption that such intervention may not be in the interest of the prospective child seems unjustified. For the other special patient groups, no conclusions could be drawn, because of a lack of relevant studies.

Endocrine profiles after triggering of final oocyte maturation with GnRH agonist after cotreatment with the GnRH antagonist ganirelix during ovarian hyperstimulation for in vitro fertilization (Article)

2002-01-01T00:00:00Z

In a randomized multicenter study, the efficacies of two different GnRH agonists were compared with that of hCG for triggering final stages of oocyte maturation after ovarian hyperstimulation for in vitro fertilization. Ovarian stimulation was conducted by recombinant FSH (Puregon), and the GnRH antagonist ganirelix (Orgalutran) was coadministered for the prevention of a premature LH rise. Luteal support was provided by daily progestin administration. Frequent blood sampling was performed at midcycle in the first 47 eligible subjects included in the current study, who were randomized for a single dose of 0.2 mg triptorelin (n = 17), 0.5 mg leuprorelin (n = 15), or 10,000 IU hCG (n = 15). Serum concentrations of LH, FSH, E2, and progesterone (P) were assessed at variable intervals. LH peaked at 4 h after both triptorelin and leuprorelin administration, with median LH levels of 130 and 107 IU/liter (P < 0.001), respectively. LH levels returned to baseline after 24 h. Subjects receiving hCG showed peak levels of 240 IU/liter hCG 24 h after administration. A rise in FSH to 19 IU/liter (P < 0.001) was noted in both GnRH agonist groups 8 h after injection. Within 24 h the areas under the curve for LH and FSH were significantly higher (P < 0.001) in both GnRH agonist groups compared with that for hCG. E2 and P levels were similar for all groups up to the day of oocyte retrieval. Luteal phase areas under the curve for P and E2 were significantly elevated (P < 0.001) in the hCG group. The mean (+/-SD) numbers of oocytes retrieved were 9.8 +/- 5.4, 8.7 +/- 4.5, and 8.3 +/- 3.3; the percentages of metaphase II oocytes were 72%, 85%, and 86%; and fertilization rates were 61%, 62%, and 56% in the triptorelin, leuprorelin, and hCG group, respectively (P = NS for all three comparisons). These findings support the effective induction of final oocyte maturation in both GnRH agonist groups. In summary, after treatment with the GnRH antagonist ganirelix for the prevention of premature LH surges, triggering of final stages of oocyte maturation can be induced effectively by a single bolus injection of GnRH agonist, as demonstrated by the induced endogenous LH and FSH surge and the quality and fertilization rate of recovered oocytes. Moreover, corpus luteum formation is induced by GnRH agonists with luteal phase steroid levels closer to the physiological range compared with hCG. This more physiological approach for inducing oocyte maturation may represent a successful and safer alternative for in vitro fertilization patients undergoing ovarian hyperstimulation.

Alternative approaches in IVF (Article)

2002-01-01T00:00:00Z

Various new developments in clinical and basic science which may impact on IVF in the near or distant future will be discussed in this review. These key areas include the regulation of early follicle development and the extended in-vitro culture of oocytes and embryos. Moreover, alternative compounds and ovarian stimulation protocols will be discussed, along with highlights in the development of the cryopreservation of excess oocytes or embryos. Finally, the health economics of IVF is addressed.

Residual ovarian activity during oral steroid contraception (Article)

2002-01-01T00:00:00Z

Steroid drugs with contraceptive properties have been available in the clinical setting for over four decades and are still subject to improvement. Estrogens, progestins and anti-progestins have been used alone or in various combinations, regimens and routes of administration to favour the balance between efficacy and undesirable effects. One of the most important changes in this respect is the gradual lowering of steroid dosage in commercially available contraceptives. Current steroid contraceptive pills still achieve the goal of suppression of pituitary-ovarian activity, but the margins for error are minimal. In this review the available data on modes of action and the effects on suppressing pituitary-ovarian activity by different forms of oral contraception are reassessed. Although pregnancy rates provide a crude measure of contraceptive efficacy, no benchmark for pituitary-ovarian inhibition is available to test the suppressive potential of contraceptive drugs. Consequently, many studies provide incomplete and/or incomparable results. For the further study of those forms of steroid contraception that rely predominantly on suppression of ovarian activity, prevention of dominant follicles selection should be the objective.

A prospective randomized comparison of sequential versus monoculture systems for in-vitro human blastocyst development (Article)

2002-01-01T00:00:00Z

BACKGROUND: Extending the period of in-vitro culture to the blastocyst stage may improve implantation rates in IVF treatment. Recognition of the dynamic nature of early embryo metabolism has led to the development of commercially available sequential culture systems. However, their improved efficacy over monoculture systems remains to be demonstrated in prospective studies. METHODS: Embryos obtained from 158 women undergoing IVF treatment were randomized by sealed envelopes to culture in one of three systems: (A) culture for 5 days in our own monoculture medium (Rotterdam medium); (B) culture for 3 days in Rotterdam medium followed by 2 days in fresh Rotterdam medium; (C) culture for 5 days using the commercially available G1/G2 sequential culture system. RESULTS: There were no significant differences in blastulation, implantation or pregnancy rates between the three tested culture systems. CONCLUSION: The employed monoculture system is as effective as the G1/G2 sequential system for the culture of blastocysts for IVF.

Low-dose exogenous FSH initiated during the early, mid or late follicular phase can induce multiple dominant follicle development (Article)

2001-01-01T00:00:00Z

This prospective, randomized trial in normo-ovulatory women was designed to test whether administration of low-dose exogenous FSH initiated during the early, mid to late follicular phase can induce multiple dominant follicle development. Forty normal weight women (age 19-35 years, cycle length 25-32 days) participated. A fixed dose (75 IU/day) of recombinant FSH was started on either cycle day 3 (n = 13), 5 (n = 13) or 7 (n = 14) until the induction of ovulation with human chorionic gonadotrophin. Frequent transvaginal ultrasound scans and blood sampling were performed. Multifollicular growth occurred in all groups (overall in 60%), although day 7 starters showed less multifollicular growth. Age, cycle length and initial FSH and inhibin B concentrations were similar between subjects with single or multiple follicle development. However, for all women the lower the body mass index (BMI), the more follicles emerged (r = -0.44, P = 0.007). If multifollicular growth occurred, the length of the luteal phase was reduced (P = 0.002) and midluteal serum concentrations of LH (P = 0.03) and FSH (P = 0.004) were decreased and oestradiol (P = 0.002) and inhibin A (P = 0.01) were increased. In conclusion, interference with decremental serum FSH concentrations by administration of low dose FSH starting on cycle day 3, 5 or as late as day 7, is capable of disrupting single dominant follicle selection. The role of BMI in determining ovarian response suggests that differences in pharmacokinetics of exogenous FSH are involved. Multifollicular growth per se has a distinct effect on luteal phase characteristics. These observations may be relevant for the design of mild ovarian stimulation protocols.

Dynamics of ovarian function in an adult woman with McCune--Albright syndrome (Article)

2001-01-01T00:00:00Z

Absent biologically relevant associations between serum inhibin B concentrations and characteristics of polycystic ovary syndrome in normogonadotrophic anovulatory infertility (Article)

2001-01-01T00:00:00Z

BACKGROUND: Dominant follicle selection is disturbed in normogonadotrophic anovulatory infertility [World Health Organization (WHO) 2] and remaining early antral follicles are either healthy or atretic. This study was conducted to investigate whether inhibin B serum concentrations (produced by healthy small antral follicles) represent the extent of ovarian abnormalities in WHO 2 women and patients with polycystic ovarian syndrome (PCOS), constituting a subgroup of WHO 2 patients. METHODS AND RESULTS: Ultrasonographic and endocrine characteristics in 379 WHO 2 patients and 30 normo-ovulatory controls were compared. In the WHO 2 patients, the PCOS subgroup and the controls, inhibin B concentrations were similar. Inhibin B concentrations were weakly but significantly correlated with the total number of ovarian follicles (r = 0.282; P < 0.001), LH (r = 0.347; P < 0.001), and testosterone (r = 0.269; P < 0.001) but not with serum oestradiol concentrations (r = 0.057). Most (71%) patients with elevated inhibin B also presented with increased concentrations of LH and/or hyperandrogenaemia. In a subgroup of 190 subjects, classified as PCOS based on hyperandrogenaemia and polycystic ovaries, elevated inhibin B concentrations were found in 23% of cases. Aforementioned correlations were similar in PCOS as in WHO 2 patients. CONCLUSION: In conclusion, inhibin B serum concentrations are normal in WHO 2 and PCOS women, suggesting a normal number of healthy early antral follicles despite increased overall follicle numbers in PCOS.

Age-related differences in features associated with polycystic ovary syndrome in normogonadotrophic oligo-amenorrhoeic infertile women of reproductive years (Article)

2001-01-01T00:00:00Z

OBJECTIVE: To assess the effect of age on clinical, endocrine and sonographic features associated with polycystic ovary syndrome (PCOS) in normogonadotrophic anovulatory infertile women of reproductive years. DESIGN: Cross-sectional study. METHODS: Four hundred and seventy-two oligo-amenorrhoeic infertile patients, presenting with normal FSH and oestradiol concentrations, aged 17-42 years underwent a standardised initial evaluation including: cycle history, body mass index, waist-to-hip ratio and transvaginal ultrasound scanning of ovaries. Fasting blood samples were obtained for extensive endocrine evaluation. Cycle duration, serum levels of gonadotrophins, androgens, oestradiol, insulin, glucose, inhibin B as well as mean number of follicles, ovarian volume and ovarian stroma echogenicity were assessed. RESULTS: Older women had significantly lower LH and androgen and inhibin B serum levels. Similarly, older women presented with a reduced number of ovarian follicles. Age was inversely correlated with cycle duration (r=-0.112, P=0.02), LH (r=-0.154, P=0.001), testosterone (r=-0.194, P=0.001), androstenedione (r=-0.170, P=0.001), dehydroepiandrosterone (r=-0.157, P=0.001), insulin (r=-0.126, P=0.02), inhibin B (r=-0.118, P=0.03) serum levels and mean follicle number (r=-0.100, P=0.03). A positive correlation was observed between age and glucose to insulin ratio (r=0.138, P=0.009). CONCLUSIONS: Advanced age in normogonadotrophic anovulatory infertile women is associated with lower LH and androgen levels and with a decreased number of ovarian follicles. Although during reproductive years observed differences are relatively small, these age-related changes may affect the observed incidence of PCOS.

Follicular and luteal phase characteristics following early cessation of gonadotrophin-releasing hormone agonist during ovarian stimulation for in-vitro fertilization (Article)

2000-01-01T00:00:00Z

Gonadotrophin-releasing hormone agonists (GnRHa) are widely used in in-vitro fertilization (IVF) for the prevention of a premature rise in luteinizing hormone (LH) concentrations. However, the administration of GnRHa during the follicular phase may also impair subsequent luteal function due to retarded recovery of pituitary gonadotrophin secretion. Therefore, luteal supplementation is generally applied. The present study was designed to determine whether a premature LH surge would still be prevented after early cessation of GnRHa during ovarian stimulation and whether subsequent luteal phase LH production would be sufficient to support progesterone synthesis by the corpus luteum. Sixty patients were randomized for three groups: (i) A long GnRHa/human menopausal gonadotrophin (HMG) protocol with luteal support by repeated human chorionic gonadotrophin (HCG) (n = 20), (ii) early follicular phase cessation of GnRHa without luteal support (n = 20), and (iii) a long GnRHa protocol without luteal support (n = 20). Frequent ultrasound and blood sampling was performed during the entire IVF cycle. Forty normo-ovulatory women served as controls. No premature LH surges were found after early cessation of GnRHa. In this group, some pituitary recovery occurred during the late luteal phase, but this did not affect corpus luteum function. Progesterone concentrations were shown to be dependent on disappearance of the pre-ovulatory bolus of HCG. Pregnancies occurred in all three groups. In conclusion, early follicular phase cessation of GnRHa is still effective in the prevention of a premature rise in LH. Although some pituitary recovery was observed thereafter, corpus luteum function is still abnormal due to early luteolysis.

Single monthly administration of the anti-progestagen Org 31710 in users of the 75 microg desogestrel progestagen-only pill: effects on pituitary-ovarian activity (Article)

2000-01-01T00:00:00Z

Endocrine and ultrasound effects were studied of an intermittent (every 28 days) oral administration of 150 mg of the anti-progestagen Org 31710 during the continued daily use of 75 microg desogestrel (DSG) for progestagen-only contraception. A randomized, double-blind, placebo-controlled two-centre study was conducted in 50 healthy volunteers. Serum luteinizing hormone (LH), follicle stimulating hormone (FSH), oestradiol and progesterone concentrations, and follicle number and size were studied, as well as endometrial thickness, which was assessed by transvaginal sonography at least twice weekly during a single medication cycle (cycle 3-5). Forty-eight women were evaluated (Org 31710, n = 25; placebo, n = 23). Seven ovulations were observed in the treated group versus none in the placebo group. LH concentrations were higher on days 9 and 11 and oestradiol concentrations lower on day 3 in the treated group, irrespective of whether ovulation occurred. No parameter could predict ovulation. Endometrial thickness was greater on cycle days 7-13 and 19 in the treated group. However, within the Org 31710 group, no significant differences were found in volunteers who did or did not ovulate. Observed differences may be attributed to a competitive effect of Org 31710 with progestagen-induced suppression of the pituitary-ovarian axis, altered oestradiol feedback mechanisms, and/or altered receptor availability.

Free androgen index and leptin are the most prominent endocrine predictors of ovarian response during clomiphene citrate induction of ovulation in normogonadotropic oligoamenorrheic infertility (Article)

2000-01-01T00:00:00Z

We have previously demonstrated that obese hyperandrogenic amenorrheic women are less likely to ovulate after clomiphene citrate (CC) medication. The present study was designed to identify whether additional endocrine screening characteristics, all potentially involved in ovarian dysfunction in 182 normogonadotropic oligoamenorrheic infertile women, are associated with ovarian response, which may improve overall prediction of CC-resistant anovulation. Standardized endocrine screening took place before initiation of CC medication (50 mg/day; increasing doses up to 150 mg/day if required) from cycle days 3-7. Screening included serum assays for fasting insulin and glucose, insulin-like growth factor I (IGF-I), IGF-binding protein-1 (IGFBP-1), IGFBP-3, free IGF-I, inhibin B, leptin, and vascular endothelial growth factor. Forty-two women (22% of the total group) did not ovulate at the end of follow-up (a total number of 325 cycles were analyzed). Fasting serum insulin, insulin/glucose ratio, IGFBP-1, and leptin were all significantly different in univariate analyses (P < or = 0.02), comparing CC responders vs. nonresponders. Forward stepwise multivariate analyses in combination with factors reported earlier for prediction of patients remaining anovulatory after CC revealed a prediction model including 1) free androgen index (FAI = testosterone/sex hormone-binding globulin ratio), 2) cycle history (oligomenorrhea or amenorrhea), 3) leptin level, and 4) mean ovarian volume. These data suggest that decreased insulin sensitivity, hyperandrogenemia, and obesity, all associated with polycystic ovary syndrome, are prominent factors involved in ovarian dysfunction, preventing these ovaries from responding to stimulation by raised endogenous FSH levels due to CC medication. By using leptin instead of body mass index or waist to hip ratio, the previous model for prediction of patients remaining anovulatory after CC medication could be slightly improved (area under the curve from 0.82-0.85). This may indicate that leptin is more directly involved in ovarian dysfunction in these patients. The capability of insulin and IGFBP-1 to predict patients who remain anovulatory after CC disappears when FAI enters into the model due to a significant correlation between FAI and these endocrine parameters. This suggests that markers for insulin sensitivity (e.g. IGFBP-1 and insulin) are associated with abnormal ovarian function through its correlation with androgens, whereas leptin is directly involved in ovarian dysfunction.

Regulation of follicle development and novel approaches to ovarian stimulation for IVF (Article)

2000-01-01T00:00:00Z

Current ovarian stimulation regimens for IVF are complex and not without risk. Increasing our knowledge of the physiology of follicle development and dominant follicle selection may enable the design of less complex, safer and cheaper ovarian stimulation regimens for IVF. Decremental serum FSH concentrations during the follicular phase of the menstrual cycle are required for single dominant follicle selection. Only the most mature follicle will continue its development due to increased sensitivity for stimulation by FSH. FSH stimulation becomes insufficient for less mature follicles and remaining cohort follicles will therefore go into atresia. The number of days during which FSH is above the threshold for stimulation of follicle development is limited, resulting in a narrow FSH window. More medium sized and large pre-ovulatory follicles and increased oestradiol output can be induced by the administration of small doses of exogenous FSH during the mid- to late follicular phase, preventing the physiological decrease in FSH stimulation. Intervention with decremental serum FSH concentrations in combination with gonadotrophin-releasing hormone (GnRH) antagonists to prevent a premature rise in serum LH may induce ongoing growth of multiple follicles sufficient for IVF. The benefits and risks of these minimal hyperstimulation protocols require further evaluation.

Predictors of chances to conceive in ovulatory patients during clomiphene citrate induction of ovulation in normogonadotropic oligoamenorrheic infertility (Article)

1999-01-01T00:00:00Z

The present prospective follow-up study was designed to identify whether clinical, endocrine, or ultrasound characteristics assessed by standardized initial screening of normogonadotropic oligo/amenorrheic infertile patients could predict conception in 160 women who reached ovulation after clomiphene citrate (CC) medication. Additional inclusion criteria were total motile sperm count of the partner above 1 million and a negative history for any tubal disease. Daily CC doses of 50 mg (increasing up to 150 mg in case of absent ovarian response) from cycle days 3-7 were used. First conception (defined as a positive urinary pregnancy test) was the end point for this study. A cumulative conception rate of 73% was reached within 9 CC-induced ovulatory cycles. Patients who did conceive presented more frequently with lower age (P < 0.0001) and amenorrhea (P < 0.05) upon initial screening. In a univariate analysis, patients with elevated initial serum LH concentrations (>7.0 IU/L) had a higher probability of conceiving (P < 0.01). In a multivariate analysis, age and cycle history (oligomenorrhea vs. amenorrhea) were identified as the only significant parameters for prediction of conception. These observations suggest that there is more to be gained from CC ovulation induction in younger women presenting with profound oligomenorrhea or amenorrhea. Screening characteristics involved in the prediction of ovulation after CC medication in normogonadotropic oligo/amenorrheic patients (body weight and hyperandrogenemia, as shown previously) are distinctly different from predictors of conception in ovulatory CC patients (age and the severity of cycle abnormality). This disparity suggests that the FSH threshold (magnitude of FSH required for stimulation of ongoing follicle growth and ovulation) and oocyte quality (chances for conception in ovulatory cycles) may be differentially regulated.

Elevated serum levels of free insulin-like growth factor I in polycystic ovary syndrome (Article)

1999-01-01T00:00:00Z

Polycystic ovary syndrome (PCOS) is the most common cause of anovulation in women. Previous studies suggest that the pathogenesis of PCOS may involve interrelated abnormalities of the insulin-like growth factor (IGF) and ovarian steroidogenesis systems. We investigated this hypothesis in fasting serum samples from 140 women with PCOS (age, 27.4 +/- 0.4 yr; body mass index, 26.3 +/- 0.5 kg/m2; mean +/- SEM). IGF-related parameters were also studied in a group of normoovulatory women (n = 26; age, 26 +/- 4 yr; body mass index, 23.6 +/- 4.3 kg/m2). For the PCOS group, the mean testosterone (T) level was 2.5 +/- 0.1 nmol/L, and it was significantly correlated with LH (r = 0.41; P < 10(-6)), estrone (r = 0.33; P = 0.016), estradiol (r = 0.18; P = 0.04), and androstenedione (AD; P < 10(-6)), but not with dehydroepiandrosterone sulfate (P = 0.71), a marker of adrenal steroidogenesis. T and AD were also related to total ovarian follicle number and ovarian size, as previously found with normoovulatory women (1). There were no differences between the PCOS subjects and the normoovulatory group for total IGF-I, IGF-II, or IGF-binding protein-3 (IGFBP-3). However, IGFBP-1 levels were significantly decreased in the PCOS group (1.0 +/- 0.2 vs. 7.3 +/- 1.1 ng/mL; P < 0.001) and were inversely correlated with serum insulin levels (r = -0.50; P < 10(-8)). Serum levels of free IGF-I (fIGF-I) were elevated (5.9 +/- 0.3 vs. 2.7 +/- 0.3 ng/mL; P < 0.001) in inverse relation with IGFBP-1 (r = -0.31; P = 0.046). Serum fIGF-I levels were related to total follicle number (r = - 0.35; P < 10(-4)) and to the ratio of sex hormone-binding globulin to T (r = -0.23; P = 0.009). However, these relationships were not independent of other variables. Despite the more than 2-fold elevation in fIGF-I levels, significant relationships between fIGF-I and markers of ovarian steroidogenesis (T, AD, estradiol, and estrone) could not be demonstrated. In conclusion, although we confirmed correlations between LH and hyperandrogenemia and have found abnormalities in the IGF system in a large cohort of PCOS subjects, a direct relationship between hyperandrogenism and the IGF system could not be shown. Previous studies suggest that elevated LH and hyperinsulinemia lead to excess ovarian androgen synthesis in PCOS and that the intraovarian IGF system is important for normal follicle development and may be important in the arrested state of follicle development in PCOS. However, the data presented in this cross-sectional study suggest that insulin-related changes in circulating IGFBP-1 and subsequent elevation of fIGF-I reflect insulin resistance and have little enhancing effects on ovarian steroidogenesis in this disorder.

Zorg rondom de voortplanting: luxe geneeskunde? (Inaugural Lecture)

1998-01-29T00:00:00Z

The follicle-stimulating hormone (FSH) threshold/window concept examined by different interventions with exogenous FSH during the follicular phase of the normal menstrual cycle: duration, rather than magnitude, of FSH increase affects follicle development (Article)

1998-01-01T00:00:00Z

According to the threshold concept, FSH concentrations need to surpass a distinct level to stimulate ovarian follicle growth. The window concept stresses the significance of a limited duration of elevated FSH levels above the threshold for single dominant follicle selection. The aim of this study was to investigate effects on follicle growth of increased FSH levels, differing in duration and magnitude of elevation, during the follicular phase. Twenty-three normo-ovulatory (cycle length, 26-31 days), young (age, 20-31 yr) women volunteered for this study. In all subjects a series of daily transvaginal sonography scans of the ovaries and blood sampling [for FSH and estradiol (E2) determinations] were performed during two consecutive cycles. The first study cycle (control cycle) started 10 days after urinary assessment of the LH surge in the preceding cycle (DayLH) and was concluded on the day of ovulation assessed by transvaginal sonography scans. The second series of daily monitoring (intervention cycle) started 10 days after DayLH in the control cycle. After randomization, subjects received either 375 IU urinary FSH, s.c., as a single injection on Day(LH+14) (group A; n = 11) or 75 IU daily from Day(LH+19) until Day(LH+23) (group B; n = 12). In group A, FSH levels increased on the day after injection to a median concentration of 10.1 IU/L, which was 1.9 times higher (P < 0.01) than levels on matching days during the control cycle. Concentrations returned to basal levels 3 days after injection. In group B, a moderate elevation of FSH concentrations (15% increase; P < 0.05) was observed compared to levels during the control cycle. In group A, E2 concentrations increased (P = 0.03) 1 day after FSH injection and returned to baseline levels within 2 days. In group B, E2 levels started to increase after the first injection of FSH and remained significantly higher (P < 0.01) during the following 5 days compared to those on matching days in the control cycle. Compared to matching days in the control cycle an increased number of follicles 8-10 mm in size was found in group A (P < 0.01) during the period from Day(LH+14) until Day(LH+19), without an increase in follicles 10 mm or larger thereafter. In contrast, in group B, the numbers of both 8- to 10-mm and 10-mm or larger follicles were higher during the period from Day(LH+19) until Day(LH+24) in group B (P = 0.02 and P < 0.01, respectively). Results from the present study suggest that a brief, but distinct, elevation of FSH levels above the threshold in the early follicular phase does not affect dominant follicle development, although the number of small antral follicles did increase. In contrast, a moderate, but continued, elevation of FSH levels during the mid to late follicular phase (effectively preventing decremental FSH concentrations) does interfere with single dominant follicle selection and induces ongoing growth of multiple follicles. These findings substantiate the FSH window concept and support the idea of enhanced sensitivity of more mature follicles for stimulation by FSH. These results may provide the basis for further investigation regarding ovulation induction treatment regimens with reduced complication rates due to overstimulation.

High dose gonadotrophin-releasing hormone antagonist (ganirelix) may prevent ovarian hyperstimulation syndrome caused by ovarian stimulation for in-vitro fertilization (Article)

1998-01-01T00:00:00Z

This case report describes the first attempt to treat imminent ovarian hyperstimulation syndrome (OHSS) by using a gonadotrophin-releasing hormone (GnRH) antagonist. A 33 year old, normo-ovulatory woman undergoing in-vitro fertilization received daily subcutaneous injections of 150 IU of recombinant follicle-stimulating hormone (recFSH) from cycle day 2, together with GnRH antagonist (ganirelix) 0.125 mg from cycle day 7 onwards. On cycle day 10 the patient was found to have a serum oestradiol concentration of 16 500 pmol/l and, on ultrasound examination, four preovulatory (>16 mm) and nine intermediate sized (10-16 mm) follicles. RecFSH injections were discontinued, human chorionic gonadotrophin (HCG) withheld, whereas the ganirelix dose was increased to 2 mg/d. This regimen led to a rapid decrease in serum oestradiol concentrations and the decrease in ovarian size on ultrasound. Since GnRH antagonists will become clinically available for in-vitro fertilization programmes in the near future this suggested regimen might have a role in preventing severe OHSS.

Predictors of patients remaining anovulatory during clomiphene citrate induction of ovulation in normogonadotropic oligoamenorrheic infertility (Article)

1998-01-01T00:00:00Z

The diagnostic criteria used to identify patients suffering from polycystic ovary syndrome remain controversial. The present prospective longitudinal follow-up study was designed to identify whether certain criteria assessed during standardized initial screening could predict the response to ovulation induction with clomiphene citrate (CC) in 201 patients presenting with oligomenorrhea or amenorrhea and infertility. Serum FSH levels were within the normal range (1-10 IU/L), and all patients underwent spontaneous or progestin-induced withdrawal bleeding. Initial CC doses were 50 mg daily for 5 days starting on cycle day 3. In the case of an absent response, doses were increased to 100 and 150 mg daily in subsequent cycles. First ovulation with CC was used as the end point. After a complete follow-up (in the case of a nonresponse, at least 3 treatment cycles with daily CC doses up to 150 mg), 156 patients (78%) ovulated. The free androgen index (FAI = testosterone/sex hormone-binding globulin ratio), body mass index (BMI), cycle history (oligomenorrhea vs. amenorrhea), serum androgen (testosterone and/or androstenedione) levels, and mean ovarian volume assessed by transvaginal sonography were all significantly different (P < 0.01) in responders from those in nonresponders. FAI was chosen to be the best predictor in univariate analysis. The area under the receiver operating characteristics curve in a multivariate prediction model including FAI, BMI, cycle history, and mean ovarian volume was 0.82. Patients whose ovaries are less likely to respond to stimulation by FSH due to CC treatment can be predicted on the basis of initial screening characteristics, such as FAI, BMI, cycle history (oligomenorrhea or amenorrhea), and mean ovarian volume. These observations may add to ongoing discussion regarding etiological factors involved in ovarian dysfunction in these patients and classification of normogonadotropic anovulatory infertile women.

Lack of correlation between maximum early follicular phase serum follicle stimulating hormone concentrations and menstrual cycle characteristics in women under the age of 35 years (Article)

1998-01-01T00:00:00Z

The gradual increase in follicle stimulating hormone (FSH) concentrations in women approaching menopause results from the depletion of the ovarian follicular pool, a process referred to as 'ovarian ageing'. This study investigates whether variable endogenous FSH concentrations, as have been observed in normo-ovulatory young women, are related to menstrual cycle characteristics, including predictors of ovarian ageing. Serum concentrations of immunoreactive FSH, oestradiol, and inhibin-A and inhibin-B were measured, and follicular growth was assessed by transvaginal ultrasound throughout the follicular phase in 39 healthy volunteers (20-35 years) with regular menstrual cycles. Median serum FSH concentration on cycle day 3 was 5.1 IU/l (range 3.6-11.2), and median maximum follicular phase FSH was 6.2 IU/l (range 4.3-11.2), observed on cycle day 6 (range 2-15). Maximum FSH concentrations were not correlated with age or cycle length, nor with maximum inhibin-B. The number of small (<10 mm) antral follicles on cycle day 3 was 11 (range 4-21) and was not correlated with age, nor with maximum FSH. Inhibin-A remained low until a significant rise on cycle day 9 (range 3-12), which was significantly correlated with the late follicular rise in oestradiol (r = 0.56, P = 0.01). These observations indicate a lack of correlation between maximum follicular phase serum FSH concentrations and parameters of ovarian ageing in women under the age of 35 years. In addition, FSH concentrations assessed on cycle day 3 represent an underestimation of maximum early follicular phase FSH. Distinct individual differences in intra-ovarian modification of FSH action, resulting in differences in the FSH threshold for stimulation of ovarian function, may be operative.

Manipulation of human ovarian function: physiological concepts and clinical consequences (Article)

1997-01-01T00:00:00Z

Low levels of follicle-stimulating hormone receptor-activation inhibitors in serum and follicular fluid from normal controls and anovulatory patients with or without polycystic ovary syndrome (Article)

1997-01-01T00:00:00Z

In patients with normogonadotropic anovulation, either with or without polycystic ovary syndrome (PCOS), factors interfering with FSH action may be involved in arrested follicle development. The aim of this study is to assess whether factors inhibiting FSH receptor activation are elevated in serum or follicular fluid from anovulatory patients, as compared with regularly cycling women. For this purpose, a Chinese hamster ovary cell line, stably transfected with the human FSH receptor, has been applied. FSH-stimulated cAMP secretion in culture medium was measured in the presence of serum or follicular fluid. Chinese hamster ovary cells were stimulated with a fixed concentration of FSH (3 or 6 mIU/mL) to mimic FSH levels in serum or follicular fluid. Samples were added in concentrations ranging from 3-90% vol/vol to approach protein concentrations occurring in serum or follicular fluid. In the presence of 10% vol/vol serum from regularly cycling women (n = 8), FSH-stimulated cAMP production was inhibited to 42 +/- 2% (mean +/- SEM of 2 experiments, each performed in duplicate) of cAMP production in the absence of serum, whereas a similar cAMP level (up to 38 +/- 4% of the serum-free level) was observed at higher concentrations of serum (30-90% vol/vol). The inhibition of FSH-stimulated cAMP production in the presence of serum samples from normogonadotropic anovulatory patients, without (n = 13) or with (n = 16) PCOS, was similar to controls. Follicular fluid samples (n = 57) obtained during the follicular phase in 25 regularly cycling women and follicular fluid samples (n = 25) from 5 PCOS patients were tested in a slightly modified assay system. In the presence of 10 or 30% (vol/vol) follicular fluid, FSH-stimulated cAMP levels were decreased to 68 +/- 2% and 55 +/- 2% (mean +/- SEM of a single experiment in triplicate) of the cAMP levels in the absence of follicular fluid, respectively. There was no correlation between the degree of cAMP inhibition and follicle size, steroid content (androstenedione or estradiol concentrations), or menstrual cycle phase. Furthermore, no differences in inhibition were found, comparing PCOS follicles with size- and steroid content-matched follicles obtained during the normal follicular phase. It is concluded that inhibition of FSH receptor activation by proteins present in serum or follicular fluid is constant (60 and 40%, respectively) and independent from the developmental stage of the follicle, either during the normal follicular phase or in patients with normogonadotropic anovulation. Inhibition of FSH receptor activation may be of limited significance for normal and arrested follicle development.

Follicular development and oocyte maturation in hypogonadotrophic women employing recombinant follicle-stimulating hormone: the role of oestradiol (Article)

1997-01-01T00:00:00Z

Both luteinizing hormone (LH) and follicle-stimulating hormone (FSH) are required for follicle development and oestrogen production. Moreover, under normal conditions a close association between dominant follicle size and serum and intrafollicular oestradiol levels is observed. With the recent availability of human recombinant FSH (recFSH), it was possible for the first time to study effects of FSH alone, in the complete absence of endogenous or exogenous LH, on ovarian function. Recent studies applying recFSH in hypogonadotrophic women have shown convincingly that normal growth of follicles up to the preovulatory stage occurs despite extremely low oestradiol levels, in keeping with previous observations using exogenous gonadotrophins in women incapable of synthesizing oestradiol due to steroid enzyme abnormalities. Insufficient data are presently available in humans to conclude whether or not oocyte quality is compromised under these circumstances. It should, however, be realized that sufficient oestradiol levels are required for fertilization in vivo. Therefore LH, or human chorionic gonadotrophin (HCG), should be added to stimulation protocols in hypogonadotrophic individuals. These observations may also be relevant for monitoring of ovarian response during recFSH therapy, especially when combined with gonadotrophin-releasing hormone agonists for ovarian hyperstimulation for in-vitro fertilization.

Urinary follicle-stimulating hormone for normogonadotropic clomiphene-resistant anovulatory infertility: prospective, randomized comparison between low dose step-up and step-down dose regimens (Article)

1997-01-01T00:00:00Z

A low dose step-up and step-down regimen for induction of ovulation using urinary FSH was compared in a prospective randomized fashion in 37 normogonadotropic clomiphene-resistant oligo- or amenorrheic infertile women. The objectives was to assess potential differences in duration of treatment, ovarian stimulation (serum FSH levels), and response [serum estradiol (E2) levels and number and size of follicles]. Monitoring (blood sampling and transvaginal sonography) took place on the day of initiation of treatment, the first day of ovarian response as assessed by ultrasound (i.e. the first day a follicle > or = 10 mm could be recognized), the day of hCG administration to induce ovulation, and 3 days thereafter. The median duration of treatment in the low dose step-up group was 18 (range, 7-41) days compared to 9 (range, 4-16) days in the step-down group (P = 0.003), and the total numbers of ampules administered were 20 (range, 7-69) and 14 (range, 7-33), respectively (P = NS). Serum FSH levels from the first day of sonographic ovarian response until the administration of hCG were constant (median increase, 2%/day) in patients receiving the low dose step-up protocol, but showed a decrease (median, 5%/day) in step-down cycles (P < 0.001). Monofollicular growth, defined as not more than one follicle 16 mm or larger on the day of hCG administration, was observed in 56% of low dose step-up and 88% of step-down cycles (P = 0.04). The percentage of patients with normal range periovulatory E2 serum levels (500-1500 pmol/L) was 33% in the low dose step-up group vs. 71% in the step-down group (P = 0.03). We conclude that a step-down protocol for gonadotropin induction of ovulation exhibits a more physiological, late follicular phase FSH serum profile than a low dose step-up protocol. This results in a shorter duration of treatment, a greater number of monofollicular cycles, and more cycles with periovulatory E2 levels within the normal range in the step-down protocol.

Interference with follicle stimulating hormone regulation of human ovarian function (Article)

1996-01-01T00:00:00Z

This review summarizes observations on the background and potential clinical significance of interference with follicle stimulating hormone (FSH) regulation of human ovarian function. This interference may occur at the level of the pituitary by the secretion of FSH isoforms with reduced or absent bioactivity. In addition, interference with FSH may occur in the circulation, or within the ovarian follicular compartment. Although the full range of its significance remains to be elucidated, there are distinct indications that these mechanisms may be involved in normal ovarian physiology, as well as in abnormal response of the ovary to stimulation by endogenous FSH or by exogenously-administered gonadotrophin preparations. Moreover, recent advances in the determination of the structure-function relationship of FSH and FSH-receptor interaction, in combination with new developments in recombinant DNA technology, will allow the production of modified FSH- or FSH receptor-like molecules with altered bioactivity. The availability of FSH agonists and antagonists in the near future should provide a challenge for clinicians to improve treatment outcome and to find new indications for the use of these compounds.