http://repub.eur.nl/res/aut/7294/ List of Publications en http://repub.eur.nl/static-eur/img/logo.png http://repub.eur.nl http://repub.eur.nl/res/pub/10238/ 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. http://repub.eur.nl/res/pub/32024/ 2002-11-06T00:00:00Z Anovulation is a major cause of female reproductive dysfunction and can be identified in approximately 18-25% of couples presenting with infertility (Hull et al., 1985). Oligomenorrhea (arbitrarily defined as menstrual periods occurring at intervals betvveen 35 days to 6 months) or amenorrhea (menstruation intervals longer than 6 months) are common features. Whether and ho\v frequent there occasional bleedings are associated with preceding ovulatory cycles is not known. The occurence of ovulation can be established applying basal body temperature charts, the assessment of serum progesterone levels, or through the observation by ultrasound of co !laps of the pre-ovulatory follicle. While ovulatory cycles may be observed occasionally in oligomenorrheic ·women, ovulatory cycles are unlikely events in amenorrhea. 'vVell-designed longitudinal follow-up studies concerning the incidence of spontaneous conception in oligomenorrheic patients are lacking. Follov,.·-up studies performed thus far report only on pregnancies in those women who did not conceive spontaneously and subsequently seek the physician's help. Therefore, this population may be a negative selection of patients who exhibit cycle abnormalities. Obviously, induction of ovulation is required in these anovulatory patients to achieve follicular maturation, subsequent ovulation and ultimately conception. The association between oligoamenorrhea, obesity, bilateral polycystic ovaries, and hirsutism was illustrated in 1935 by Stein and Leventhal (Stein et al., 1935). A primary ovarian defect was inferred since bilateral vvedge resection of the ovary restored the cycle abnormality unexpectedly and 2 of 7 patients conceived (Stein et al., 1967). The wide variability of clinical and histologic findings associated with anovulatory state in PCOS resulted in the inability of the investigator to distinguish clinically significant and reliable characteristics of this syndrome (Goldzieher et al., 1963). Excessive androgen production was initially attributed to abnormal adrenal function. Hyperandrogenemia clue to diminished granulosa cell aromatase activity (responsible fOr the conversion of androgens to estrogens) of the polycystic ovaries (PCO) has subsequently been demonstrated (Axelrod et al., 1962). Abnormalities in the hypothalamic-pituitary-ovarian axis resulting in inappropriate FSH secretion along with luteinizing hormone (LH) hypersecretion has also been highlighted (Yen et al., 1970). Further insight in the abnormal physiology of this disorder occurred vvhen hyperandrogenism \vas demonstrated to be LH dependent (Givens et al., 1974). A landmark discovery was the association of ovarian hyperandrogenism and various causes of insulin resistance (Kahn et al., 1976) and subsequently, an association between polycystic ovaries, hyperandrogenism and hyperinsulinemia was established (Burghen et al., 1980). http://repub.eur.nl/res/pub/9661/ 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. http://repub.eur.nl/res/pub/9796/ 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. http://repub.eur.nl/res/pub/9278/ 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. http://repub.eur.nl/res/pub/9091/ 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. http://repub.eur.nl/res/pub/8861/ 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.