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Biomedical subjects

M J Eijkemans

Publications and source records attributed to M J Eijkemans.

At least 19 recordsLinked to original sources
PubMed2006

PCOS according to the Rotterdam consensus criteria: Change in prevalence among WHO-II anovulation and association with metabolic factors.

OBJECTIVE: The current report aims to compare the prevalence of polycystic ovary syndrome (PCOS) diagnosed according to the new Rotterdam criteria (Rott-PCOS) versus the previous criteria as formulated by the National Institutes of Health (NIH) (NIH-PCOS) in women with normogonadotropic (WHO-II) anovulation and assess the frequency of obesity and related factors determined in these women. DESIGN: Cohort study based on large anovulation screening database. SETTING: Two large tertiary referral centres for reproductive medicine. POPULATION: WHO-II normogonadotropic, anovulatory, infertility cases. METHODS: WHO-II cases were extracted from the screening database and classified according to both the Rotterdam and NIH criteria for PCOS. Within these two classes, the prevalence of obesity, hyperglycaemia and insulin resistance was assessed and compared and their relation to the difference in diagnostic criteria applied was analysed. MAIN OUTCOME MEASURES: Prevalence of diagnosis PCOS in the WHO-II anovulation group. Prevalence of obesity, hyperglycaemia and insulin resistance in the two diagnostic classes. RESULTS: The Rott-PCOS group appeared to be more than 1.5 times larger than the group classified as NIH-PCOS (91 versus 55% of the WHO-II cohort). Especially, women with ovarian dysfunction and polycystic ovaries at ultrasound scan, but without hyperandrogenism, were added to the PCOS diagnostic group. The Rott-PCOS exhibited a lower frequency of obesity, hyperglycaemia and insulin resistance compared with the NIH-PCOS group. Obese women in the Rott-PCOS group without androgen excess had a different metabolic profile compared with obese women in the NIH-PCOS group, with lower rates of hyperglycaemia and hyperinsulinism, despite comparable distributions of body weight. CONCLUSION: The present findings indicate that with the new Rotterdam consensus criteria, oligo/anovulatory women with less severe metabolic derangement will be added to the heterogeneous group of women with PCOS.

Anovulation↗
PubMed2001

Prognosis after aortic valve replacement with a bioprosthesis: predictions based on meta-analysis and microsimulation.

BACKGROUND: Bioprostheses are widely used as an aortic valve substitute, but knowledge about prognosis is still incomplete. The purpose of this study was to provide insight into the age-related life expectancy and actual risks of reoperation and valve-related events of patients after aortic valve replacement with a porcine bioprosthesis. METHODS AND RESULTS: We conducted a meta-analysis of 9 selected reports on stented porcine bioprostheses, including 5837 patients with a total follow-up of 31 874 patient-years. The annual rates of valve thrombosis, thromboembolism, hemorrhage, and nonstructural dysfunction were 0.03%, 0.87%, 0.38%, and 0.38%, respectively. The annual rate of endocarditis was estimated at 0.68% for >6 months of implantation and was 5 times as high during the first 6 months. Structural valve deterioration was described with a Weibull model that incorporated lower risks for older patients. These estimates were used to parameterize, calibrate, and validate a mathematical microsimulation model. The model was used to predict life expectancy and actual risks of reoperation and valve-related events after implantation for patients of different ages. For a 65-year-old male, these figures were 11.3 years, 28%, and 47%, respectively. CONCLUSIONS: The combination of meta-analysis with microsimulation enabled a detailed insight into the prognosis after aortic valve replacement with a bioprosthesis for patients of different ages. This information will be useful for patient counseling and clinical decision making. It also could serve as a baseline for the evaluation of newer valve types.

Adolescent↗
PubMed2001

Estimated event-free life expectancy after autograft aortic root replacement in adults.

BACKGROUND: Autograft aortic root replacement is an established therapeutic option for young adults with aortic valve disease. Unfortunately, most series are small with a limited follow-up. Meta-analysis and microsimulation modeling were used to predict long-term outcome based on currently available midterm data. METHODS: We combined our center's experience with autograft aortic root replacement in 85 adult patients in a meta-analysis with reported results of three other hospitals. The outcomes of this meta-analysis were entered in a microsimulation model, calculating (event-free) life expectancy after autograft aortic root replacement. RESULTS: The pooled results comprised 380 patients with a total follow-up of 1,077 patient-years. Mean age was 37 years (range 16 to 68 years). Male/female ratio was 2.7. Operative mortality was 2.6% (n = 10); during follow-up 6 more patients died. Linearized annual risk estimates were 0.5% for thromboembolism, 0.3% for endocarditis, and 0.4% for nonstructural valve failure. Structural autograft failure requiring reoperation occurred in 5 patients, and a Weibull function was constructed accordingly. Using this information, the microsimulation model predicted age- and gender-specific mean, reoperation-free, and event-free life expectancy. CONCLUSIONS: Based on current evidence the calculated average autograft-related reoperation-free life expectancy is 16 years. The combination of meta-analysis and microsimulation provides a promising and powerful tool for estimating long-term outcome after aortic valve replacement.

Adolescent↗
PubMed2001

Dynamics of the development of multiple follicles during ovarian stimulation for in vitro fertilization using recombinant follicle-stimulating hormone (Puregon) and various doses of the gonadotropin-releasing hormone antagonist ganirelix (Orgalutran/Antagon).

OBJECTIVE: To investigate relations between dose of GnRH antagonist and follicular phase characteristics. DESIGN: Randomized controlled multicenter trial. SETTING: Tertiary referral fertility centers. PATIENT(S): Three hundred and twenty-nine IVF patients. INTERVENTION(S): Ovarian stimulation for IVF with recombinant FSH starting on cycle day 2. From cycle day 7 onwards, cotreatment was provided with 0.0625, 0.125, 0.25, 0.5, 1.0, or 2.0 mg/d GnRH antagonist. MAIN OUTCOME MEASURE(S): Number of follicles, total follicular surface area, gonadotropin, and serum steroid concentrations. RESULT(S): In 311 patients, similar follicular growth was observed in all treatment groups. FSH levels increased during the follicular phase. Late follicular phase LH, androstenedione (AD), and E(2) levels showed a GnRH antagonist dose-related decrease (P<0.05). Late follicular phase E(2) levels correlated with total follicular surface area, AD, LH, and FSH (all P<0.001). Increasing GnRH antagonist doses exhibited additional suppressive action on E(2) levels. CONCLUSION(S): Follicular growth was unaffected by the dose of GnRH antagonist. A rise in follicular phase FSH serum concentrations during the follicular phase, largely related to exogenous FSH, enabled ongoing follicular growth in all treatment groups. The effect of GnRH antagonist on late follicular phase E(2) levels could not be exclusively attributed to suppression of LH.

Adolescent↗
PubMed2001

Internal validation of predictive models: efficiency of some procedures for logistic regression analysis.

The performance of a predictive model is overestimated when simply determined on the sample of subjects that was used to construct the model. Several internal validation methods are available that aim to provide a more accurate estimate of model performance in new subjects. We evaluated several variants of split-sample, cross-validation and bootstrapping methods with a logistic regression model that included eight predictors for 30-day mortality after an acute myocardial infarction. Random samples with a size between n = 572 and n = 9165 were drawn from a large data set (GUSTO-I; n = 40,830; 2851 deaths) to reflect modeling in data sets with between 5 and 80 events per variable. Independent performance was determined on the remaining subjects. Performance measures included discriminative ability, calibration and overall accuracy. We found that split-sample analyses gave overly pessimistic estimates of performance, with large variability. Cross-validation on 10% of the sample had low bias and low variability, but was not suitable for all performance measures. Internal validity could best be estimated with bootstrapping, which provided stable estimates with low bias. We conclude that split-sample validation is inefficient, and recommend bootstrapping for estimation of internal validity of a predictive logistic regression model.

Aged↗
PubMed2001

Somatostatin receptor scintigraphy useful in stage I-II Hodgkin's disease: more extended disease identified.

Somatostatin receptor (SS-R) scintigraphy successfully shows primary cancers and metastases in patients with a variety of SS-R-positive tumours. In vitro studies have shown that SS-Rs are present in lymph nodes from patients with Hodgkin's disease (HD). We performed a prospective study in 126 newly diagnosed patients with HD and compared the results of SS-R scintigraphy with conventional staging procedures, i.e. physical examination, computerized tomography (CT) scanning and other imaging techniques. We report positive scintigraphy in all patients. The lesion-related sensitivity was 94% and varied from 98% for supradiaphragmatic lesions to 67% for infradiaphragmatic lesions. In comparison with CT scanning and ultrasonography, SS-R scintigraphy provided superior results for the detection of Hodgkin's localizations above the diaphragm. In the intra-abdominal region, the CT scan was more sensitive than the SS-R scan. A false-positive scan was rarely seen. In stages I and II supradiaphragmatic HD patients, SS-R scintigraphy detected more advanced disease in 18% (15 out of 83) of patients, resulting in an upstaging to stage III or IV, thus directly influencing patient management. Our data would support the validity of SS-R scanning as a powerful imaging technique for the staging of patients with HD.

Adolescent↗
PubMed2001

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

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.

Adult↗
PubMed2001

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

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.

Adult↗
PubMed2001

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

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.

Adolescent↗
PubMed2001

Somatostatin receptor scintigraphy in the initial staging of low-grade non-Hodgkin's lymphomas.

UNLABELLED: In this prospective study, somatostatin receptor (SS-R) scintigraphy was compared with conventional staging procedures for the initial staging of patients with low-grade non-Hodgkin's lymphoma (NHL). METHODS: Fifty consecutive untreated patients with low-grade NHL underwent SS-R scintigraphy as part of their initial staging. Planar images were obtained 24 and 48 h after intravenous injection of 220 MBq (111)In-pentetreotide. SPECT images of the upper abdomen were obtained from all patients. SS-R scans were evaluated blindly without knowledge of the results of the conventional staging methods. SS-R scintigraphy findings were compared with the results of physical and radiologic examinations. RESULTS: SS-R scintigraphy findings were positive in 42 of 50 patients (84%). In 10 patients (20%), the SS-R scan revealed new lesions that had not been revealed by conventional staging procedures. These 10 patients were all upgraded to a higher stage. Consequently, the treatment plan would have been altered in 5 patients (10%). However, in 19 patients (38%), lesions apparent after conventional staging methods were missed by SS-R scintigraphy. The sensitivity of SS-R scintigraphy varied from 62% for supradiaphragmatic lesions to 44% for infradiaphragmatic lesions. The specificity of SS-R scintigraphy was high (98%-100%). In comparison with CT scanning and sonography, SS-R scintigraphy is inferior for the visualization of NHL lesions in the thorax and abdomen. CONCLUSION: Although SS-R scintigraphy findings are positive in a large proportion of patients with low-grade NHL, in most patients only part of the lesions can be visualized. Because of the limited sensitivity, we recommend SS-R scintigraphy for initial staging of patients with low-grade NHL only in selected conditions and not for the general work-up.

Female↗
PubMed2000

Prognostic modelling with logistic regression analysis: a comparison of selection and estimation methods in small data sets.

Logistic regression analysis may well be used to develop a prognostic model for a dichotomous outcome. Especially when limited data are available, it is difficult to determine an appropriate selection of covariables for inclusion in such models. Also, predictions may be improved by applying some sort of shrinkage in the estimation of regression coefficients. In this study we compare the performance of several selection and shrinkage methods in small data sets of patients with acute myocardial infarction, where we aim to predict 30-day mortality. Selection methods included backward stepwise selection with significance levels alpha of 0.01, 0.05, 0. 157 (the AIC criterion) or 0.50, and the use of qualitative external information on the sign of regression coefficients in the model. Estimation methods included standard maximum likelihood, the use of a linear shrinkage factor, penalized maximum likelihood, the Lasso, or quantitative external information on univariable regression coefficients. We found that stepwise selection with a low alpha (for example, 0.05) led to a relatively poor model performance, when evaluated on independent data. Substantially better performance was obtained with full models with a limited number of important predictors, where regression coefficients were reduced with any of the shrinkage methods. Incorporation of external information for selection and estimation improved the stability and quality of the prognostic models. We therefore recommend shrinkage methods in full models including prespecified predictors and incorporation of external information, when prognostic models are constructed in small data sets.

Age Factors↗
PubMed2000

Prognostic models based on literature and individual patient data in logistic regression analysis.

Prognostic models can be developed with multiple regression analysis of a data set containing individual patient data. Often this data set is relatively small, while previously published studies present results for larger numbers of patients. We describe a method to combine univariable regression results from the medical literature with univariable and multivariable results from the data set containing individual patient data. This 'adaptation method' exploits the generally strong correlation between univariable and multivariable regression coefficients. The method is illustrated with several logistic regression models to predict 30-day mortality in patients with acute myocardial infarction. The regression coefficients showed considerably less variability when estimated with the adaptation method, compared to standard maximum likelihood estimates. Also, model performance, as distinguished in calibration and discrimination, improved clearly when compared to models including shrunk or penalized estimates. We conclude that prognostic models may benefit substantially from explicit incorporation of literature data.

Age Factors↗
PubMed2000

Implantation rates after in vitro fertilization and transfer of a maximum of two embryos that have undergone three to five days of culture.

OBJECTIVE: To evaluate implantation and pregnancy rates in patients undergoing IVF after the transfer of a maximum of two embryos that had been cultured for 3-5 days. DESIGN: Prospective study. SETTING: An IVF laboratory at a tertiary referral university hospital. PATIENT(S): One thousand seven hundred eighty-seven couples who underwent their first IVF cycle between January 1995 and December 1997. INTERVENTION(S): In vitro fertilization and transfer of embryos after 3, 4, or 5 days of culture using a single medium without coculture. MAIN OUTCOME MEASURE(S): Implantation and pregnancy rates. RESULT(S): Overall implantation and pregnancy rates were not significantly different with different culture periods. Forty-one percent of all available embryos developed into blastocysts on day 5. The transfer of at least one good-quality blastocyst could be performed in 62% of patients. Blastocysts had an implantation rate of 26% per embryo, whereas the implantation rate of eight-cell embryos on day 3 was 18%. Implantation rates for retarded, normal, and advanced embryos were not significantly different with an extended culture period. CONCLUSION(S): Under the study conditions, the transfer of embryos after 5 days rather than 3 days of embryo culture did not change the overall implantation and pregnancy rates. The implantation potential of embryos available for transfer can be assessed better after an extended culture period. Five days of culture allows the transfer of a reduced number of embryos without decreasing overall pregnancy rates.

Adult↗
PubMed2000

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

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.

Adult↗
PubMed2000

Normal anal sphincter anatomy and age- and sex-related variations at high-spatial-resolution endoanal MR imaging.

PURPOSE: To describe the various patterns of normal sphincter anatomy as seen at endoanal magnetic resonance (MR) imaging and to assess sex- and age-related variations in the dimensions of the anal sphincter to refine the diagnosis of sphincter disorders. MATERIALS AND METHODS: Endoanal MR imaging (1.5 T) was performed in 100 healthy volunteers (50 women, 50 men) evenly distributed between ages 20 and 85 years. The essential anatomic structures were evaluated, and various patterns in men and women were recorded. The thickness of the anal sphincter muscles and the length of the anal canal were measured, and age- and sex-related correlations were studied. RESULTS: Sex-related differences included a significantly shorter external sphincter in women than in men both laterally (mean, 27.1 mm +/- 5.4 vs 28.6 mm +/- 4.3; P: <.05) and anteriorly (mean, 14.0 mm +/- 3.0 vs 27.0 mm +/- 53.0; P: <.051). The superficial transverse perineal muscle is located more superiorly in women than in men. The central perineal tendon in men is a central muscular insertion point; in women, it represents an area where muscle fibers imbricate. Age-related variations included a significant decrease in the thickness of the external sphincter in men (P: <.01). Significant decrease in the thickness of the longitudinal muscle and increase in the thickness of the internal sphincter were noted in both sexes (P: <.01). CONCLUSION: High-spatial-resolution endoanal MR imaging provides excellent visualization of pelvic floor structures. Severe atrophy as it occurs in incontinent patients should be differentiated from physiologic, age-related thinning of the external sphincter and longitudinal muscle.

Adult↗
PubMed2000

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

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.

Adult↗