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Hum. Reprod. Advance Access published online on April 2, 2008
Human Reproduction, doi:10.1093/humrep/den108
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© The Author 2008. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Relevance of anti-Mullerian hormone measurement in a routine IVF program

C. Gnoth1,2,5, A.N. Schuring3, K. Friol1, J. Tigges1, P. Mallmann2 and E. Godehardt4

1 Center for Family Planning, Gynecological Endocrinology and Reproductive Medicine, Rheydter Strasse 143, 41515 Grevenbroich, Germany 2 Department of Obstetrics and Gynecology, University of Cologne, Cologne, Germany 3 Department of Obstetrics and Gynecology, University of Muenster, Muenster, Germany 4 Biometric Research Group, Clinic for Thoracic and Cardiovascular Surgery, Heinrich-Heine University of Duesseldorf, Duesseldorf, Germany

5 Correspondence address. Tel: +49-2181-491513; Fax: +49 2181-491534; E-mail: dr.christian.gnoth{at}rmz-nrw.de


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 Funding
 Acknowledgements
 References
 
BACKGROUND: Diminished ovarian reserve has become a major cause of infertility. Anti-Mullerian hormone (AMH) seems to be a promising candidate to assess ovarian reserve and predict the response to controlled ovarian hyperstimulation (COH). This prospective study was conducted to evaluate the relevance of AMH in a routine IVF program.

METHODS: Three hundred and sixteen patients were prospectively enrolled to enter their first IVF/ICSI-cycle. Age, FSH-, inhibin B- and AMH-levels and their predictive values for ovarian response and clinical pregnancy rate were compared by discriminant analyses.

RESULTS: A total of 132 oocyte retrievals were performed. A calculated cut-off level ≤1.26 ng/ml AMH alone detected poor responders (≤4 oocytes) with a sensitivity of 97%, and there was a 98% correct prediction of normal response in COH if levels were above this threshold. With levels <0.5 ng/ml, a correct prediction of very poor response (≤2 oocytes) was possible in 88% of cases. Levels of AMH ≥0.5 ng/ml were not significantly correlated with clinical pregnancy rates.

CONCLUSIONS: AMH is a predictor of ovarian response and suitable for screening. Levels ≤1.26 ng/ml are highly predictive of reduced ovarian reserve and should be confirmed by a second line antral follicle count. Measurement of AMH supports clinical decisions, but alone it is not a suitable predictor of IVF success.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 Funding
 Acknowledgements
 References
 
Anti-Mullerian hormone (AMH) belongs to the transforming growth factor-β superfamily. In the female, it is a product of the granulosa cells from pre-antral and small antral follicles. Together with two other key players (growth and differentiation factor-9 and bone morphogenetic protein-15), it inhibits the initiation of premature follicle growth and decreases the sensitivity of follicles for the FSH-dependent selection process (Gruijters et al., 2003Go; Visser and Themmen, 2005Go; Knight and Glister, 2006Go; Visser et al., 2006Go). AMH levels are characterized by a steady decline with age from adulthood toward menopause reflecting the size of the ovarian follicle pool (van Rooij et al., 2005Go). Therefore, AMH seems to be a promising parameter for early detection of reduced ovarian reserve as well as ovarian dysfunction (Visser et al., 2006Go). The loss of follicles with increasing female age is variable and the chronological age of the ovary does not always reflect its biological and reproductive age (Fleming et al., 2006Go). Nowadays, an increasing number of female patients in their late 30s seek help for infertility problems, meaning that diminished ovarian reserve and age-related ovarian dysfunction have become a major cause of infertility. Furthermore, epidemiological surveys suggest (Nikolaou and Templeton, 2003Go) that approximately as many as 10% of women in their early 30s could be approaching their perimenopause transition. At a high risk for early ovarian exhaustion are those of our patients with a history of repeated ovarian surgery because of functional cysts and endometriosis. Numbers of such, mostly laparoscopic, interventions seem to increase continuously. Most women with reduced ovarian reserve are still displaying regular menstrual cycle characteristics that will continue normally with deterioration only becoming clinically apparent when ovarian function is already severely impaired (Burger et al., 2005Go). Thus ovarian aging and a reduced ovarian reserve can become a critical factor in infertility, without any obvious clinical symptoms. Furthermore, a substantial rise in FSH levels occurs relatively late when the perimenopausal transition is already present (Burger et al., 1999Go). On the other hand elevated FSH levels in younger women may be related to receptor polymorphisms and not reduced ovarian reserve (Schipper et al., 1998Go). Because traditional assessments of ovarian reserve such as early follicular phase FSH, inhibin B and the clomifen challenge test have low sensitivity in the early stages of reduced ovarian reserve (van Rooij et al., 2006Go), there is an urgent need for a reliable and early marker for the detection of a declining number of follicles, and prediction of spontaneous pregnancy potential and assisted reproduction technology outcome (Muttukrishna et al., 2005Go; van Rooij et al., 2006Go; La Marca et al., 2007Go; Smeenk et al., 2007Go).

From the current literature, AMH is such a promising and reliable marker, corresponding to the number of small antral follicles (Pigny et al., 2006Go; Visser et al., 2006Go) with essentially constant levels across the cycle (La Marca et al., 2006Go) and a superior intercycle reproducibility compared with that of FSH and early antral follicle count (Fanchin et al., 2005Go; Feyereisen et al., 2006Go; Hehenkamp et al., 2006Go). Very recently some studies reported a possible benefit of serum AMH-measurement in assisted reproductive programs (Tremellen et al., 2005Go; Ebner et al., 2006Go; Ficicioglu et al., 2006Go; La Marca et al., 2007Go). However, urgently needed cut-off levels of AMH for supporting clinical decisions are still missing (Freour et al., 2006Go).

We therefore carried out a larger prospective trial calculating cut-off levels and evaluating the relevance of AMH-measurement for treatment strategies and outcome in a routine IVF program of a private institute.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 Funding
 Acknowledgements
 References
 
Between 1 June 2005 and 30 June 2006, all women visiting our center of reproductive medicine for the first time, because of involuntary childlessness with at least 1 year of unprotected intercourse without pregnancy, underwent a basic infertility investigation. On Day 3–5 of the women's normal cycle, we performed a routine gynecological examination and a basic vaginal ultrasound took a basal hormone profile (FSH, LH, Prolactin, testosterone, DHEAS, TSH and SHBG) and measured AMH and inhibin B. Other variables such as socioeconomic status, medical history, parity, duration of involuntary childlessness, age and BMI were recorded in a standardized manner.

Out of all examined women, 316 patients were prospectively enrolled in our assisted-reproduction techniques (ART) program to enter their first IVF- or ICSI-cycle. The criteria for inclusion were:

  1. early follicular phase Day 3–5, FSH and AMH levels available;
  2. regular menstrual cycle pattern (cycle length >25 and <35 days);
  3. presence of both ovaries;
  4. age <45.

Main indications for ART were: male subfertility (65%), tubal pathology (12%), endometriosis (12%), idiopathic infertility (9%) with at least two unsuccessful cycles of intrauterine insemination (IUI) and repeated polyfollicular development with gonadotrophin stimulation for IUI (2%). All included patients suffered from primary infertility with an average of 3.4 years of involuntary childlessness.

On Day 3–5 of a spontaneous cycle within 3 months following the start of controlled ovarian hyperstimulation (COH), patients underwent another transvaginal ultrasound examination to exclude ovarian cysts and to count the number of antral follicles, measuring 2–5 mm as described before by others (Scheffer et al., 1999Go, 2003Go).

This study was conducted in accordance with the principles of the declaration of Helsinki and women were asked for their consent for AMH-measurement and link to their treatment outcome.

For AMH measurement, we used a sensitive ELISA (Enzyme-Linked Immunosorbent Active MIS/AMH ELISA Kit®, DSL-10-14400, Diagnostic System Laboratories, Inc./Beckman-Coulter) according to the manufacture's instructions. This highly specific mono/mono two-site ELISA uses detection and capture antibodies, with results available within 3 h. The standards cover a range from 0.05 to 15 ng/ml (Freour et al., 2007Go). The sensitivity is 0.006 ng/ml. Intra- and inter-assay coefficients of variation were <5% and <8%, respectively. Inhibin B was measured using the DSL inhibin B ELISA test using two highly specific monoclonal antibodies (sensitivity 0.007 ng/ml with intra- and inter-assay coefficients of variation <6% and <8%, respectively, DSL-10-84100, Diagnostic System Laboratories, Inc./Beckman-Coulter).

In brief, the IVF/ICSI-treatment was as follows: all patients started with a monophasic oral contraceptive pill on Day 3–5 of their cycle. Starting of COH was scheduled according to the patient's possibilities and the center's necessities. Down-regulation with either nafarelin acetate (0.4–0.6 mg/day) or triptorelin acetate (0.05 mg/day) was started with the last 3–5 pills, 10–14 days before the start of COH. Ovarian hyperstimulation was performed with either recombinant follitrophin β (rec-FSH, Puregon®, Organon/Germany) or Menogon HP® (Ferring Pharmaceuticals, Kiel/Germany). Starting doses for patients under 35 years of age were 150 IE/ml; for patients 35 and older, it was 225–300 IE/ml. After 5 days of stimulation, follicular growth was assessed by vaginal ultrasound, estradiol measurement and control of pituitary desensitization was assessed by LH measurement. The dose of rec-FSH was adjusted according to ovarian response. Patients received ovulation induction with 250 µg recombinant human choriongonadotrophin (rec-HCG, Ovitrelle®, Serono/Germany) when at least three leading follicles were ~20 mm in size. Transvaginal oocyte retrieval was performed 35 h later. Luteal support was provided with vaginal application of micronized progesterone (Utrogest®, 400 mg/day, Kade-Pharma/Germany). A maximum of two embryos were transferred in all women in their first attempt. Supernumerous zygotes were frozen according to the German embryo protection act.

The primary outcome measured in this study was the number of oocytes retrieved. According to a widespread definition, a cut-off of four or less oocytes at retrieval was regarded as poor or low ovarian response. With a mean fertilization rate of ~60%, a minimum of four oocytes is necessary to have a possible transfer of at least two embryos. Approximately 30% of the ART cycles were conducted as IVF and 70% were conducted as IVF/ICSI because of male infertility. Clinical pregnancy was considered to be the secondary outcome measure defined as a gestational sac assessed by vaginal ultrasound 1–2 weeks after a positive pregnancy test.

Data were analyzed using the SAS package, version 9, of statistical procedures (SAS Institute Inc., Cary, USA). Student's t-test was used to compare endocrine profiles and basic characteristics of the patients. To compare the relevance of different parameters for predicting ovarian reserve and clinical pregnancy rate, we first performed a step-wise discriminant analysis, followed by linear discriminant analysis to calculate the sensitivities and specificities as well as the percentages of positive and negative predictions. For AMH alone, cut-off values and receiver operating characteristic (ROC) curves were calculated (Fawcett, 2004) to minimize both the false positive and false negative rates in order to find an optimal threshold for the discrimination between women with poor and normal response (>4 oocytes) and clinical pregnancy versus no pregnancy. The calculation of the ROC curves was based on the statistical package R. Statistical significance was considered to be reached at P-values of <0.05.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 Funding
 Acknowledgements
 References
 
In this prospective study, 316 patients were admitted to our IVF program with the aim of having their first IVF or IVF/ICSI attempt between 1 June 2005 and 30 June 2006. Out of these, 132 patients had their first oocyte retrieval in this time interval. There were no cycle cancelations because of impending ovarian hyperstimulation syndrome or no ovarian response. For 119 patients, pregnancy tests and assessments for clinical pregnancy (completed cycles) could be performed before 1 October 2006. From these, 56 clinical pregnancies were diagnosed corresponding to a clinical pregnancy rate per completed cycle of (56/119) 47%. Thirteen tests were performed after the 1st of October and not included in the further analysis. A flow chart of the 316 patients admitted and further details are presented in Fig. 1. The remaining 184 couples did not start their first cycle because of personal reasons (mainly: clarification of the coverage of treatment costs and/or occupational activity) and were treated later according to a changed protocol (see below). There was no statistical difference in the composition of these non-starters (length of infertility, age, cause of infertility and hormonal levels) and the 119 starters. No pregnancy test was missed in the 119 completed cycles. As expected, non-pregnant women and those with less than five oocytes were significantly older than pregnant women or normal responders.


Figure 1
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  		Figure 1: Flowchart of 316 ART patients with 132 oocyte retrievals and 119 completed cycles (means and standard deviations).

 
The mean AMH level of all treated patients was 1.7 ± 2.9 ng/ml. To investigate the correlation of AMH with poor ovarian response, we used step-wise and linear discriminant analyses and calculated an AMH cut-off level for poor ovarian response of ≤1.26 ng/ml with minimized false positive and false negative results. Figure 2 shows the typical ROC for AMH indicating poor ovarian response and clinical pregnancy.


Figure 2
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  		Figure 2: Receiver operating characteristic (ROC)-curves for AMH as an indicator for poor ovarian response and clinical pregnancy.

 
Table I gives the results for the stepwise discriminant analysis for poor responders (≤4 oocytes, cut-off level AMH ≤1.26 ng/ml). AMH alone showed the best performance by detecting 32 of true 33 poor responders (sensitivity). Age, FSH, inhibin B alone or in combinations were less precise. As to be expected, the specificity for identifying poor responders was improved by the use of a combination of parameters. In correctly predicting ‘normal’ ovarian response, AMH alone, using a calculated cut-off of AMH >1.26 ng/ml, was superior to the other parameters or their different combinations. Applying this model, only 2% of women with an AMH >1.26 ng/ml will have four or less oocytes in IVF following COH. Using a cut-off level of AMH ≤1.26 ng/ml, a correct prediction of ‘poor’ response was only possible in 36% of the cases mainly because of the age-related high heterogeneity between the poor and normal responder groups and probably dose adjustment during COH (see Discussion). To address this problem, both groups were adjusted for age in an additional analysis with a different statistical approach. In this way, the specificity for AMH alone increased to 62% and the correct prediction rate for poor response increased to 88%. Both sensitivity and prediction of normal response with AMH alone were much more robust and remained unchanged with or without adjustment for age (Table I). Using a level of AMH <0.5 ng/ml, a similarly robust and correct prediction of very poor response (≤2 oocytes retrieved) was possible in 88% of cases regardless of adjustment for age (Table I).


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  		Table I. Detection and prediction of poor responders (n = 33 with ≤4 oocytes, calculated cut-off AMH ≤1.26 ng/ml) in 132 oocyte retrievals.

 
Table II gives the results of the stepwise discriminant analysis for age, FSH and AMH for ‘not’ achieving pregnancy. The cut-off level minimizing for false positive and false negative failures was calculated as ≤1.8 ng/ml (Fig. 2). Neither AMH alone nor one of the other analyzed parameters alone or their combinations were suitable for predicting the success of ART cycles.


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  		Table II. Prediction of ‘no pregnancy’ in 119 complete ART cycles (cut-off: AMH ≤ 1.8 ng/ml, n = 63 unsuccessful cycles).

 
Table III shows the results of the logistic regression analysis for low and normal ovarian response in ART cycles and for AMH with a cut-off level of 1.26 ng/ml. As expected, low responders were significantly older and had a significantly lower clinical pregnancy rate with a significantly lower AMH, than normal responders. In the poor responder group, FSH was elevated but still within the normal range and was weakly achieving statistical significance (P = 0.034) in discriminating between low and normal responders. The overall clinical pregnancy rate in the low-AMH group (AMH ≤ 1.26 ng/ml) was not significantly different from the group with levels above the cut-off.


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  		Table III. Logistic regression analysis for low and normal ovarian response in ART cycles and for AMH using 1.26 ng/ml as a cut-off level.

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
Funding
 Acknowledgements
 References
 
This prospective study was conducted to evaluate the relevance of routine AMH measurements before IVF. Therefore, 316 patients were prospectively enrolled to enter their first IVF or IVF/ICSI-cycle. Age, FSH-, inhibin B- and AMH-levels and their predictive values for ovarian response and clinical pregnancy rate were compared by discriminant analyses. A total of 132 oocyte retrievals were performed. Hundred and eighty-four couples did not start their first cycle in the scheduled observation period because of individual reasons and were, after a preliminary analysis of the data already collected, treated later following a changed protocol (see below), facilitating our clinical management. Although the number of patients of the study group was relatively small, the results seemed to be promising and, according to power calculations, would not be significantly changed with increasing size of the treatment group.

A significant correlation of AMH levels with ovarian response as expressed by the number of oocytes retrieved during the first IVF or IVF/ICSI treatment cycle has been observed. Cut-off levels for clinical decisions were calculated. The ovarian response to high levels of gonadotrophins reflects the size of the cohort of selectable antral follicles. Because the number of antral follicles is related to the size of the primordial follicle pool (Gougeon et al., 1994Go), the ovarian response to stimulation reflects the ovarian reserve (Lawson et al., 2003Go). Our results show that age and AMH levels are the superior parameters predicting ovarian response. However, even in women of comparable age, there was a wide variation in the individual ovarian reserve (te Velde and Pearson, 2002Go; Gnoth et al., 2003Go; van Rooij et al., 2005Go). For them, AMH is a very promising and possibly the best actual candidate to evaluate their individual ovarian response to gonadotrophin stimulation and to detect poor responders with levels of AMH ≤1.26 ng/ml (97% sensitivity). With an AMH >1.26 ng/ml, a correct prediction of normal response (>4 oocytes) to gonadotrophin stimulation of 98% can be achieved. Combinations of age and serum parameters FSH, inhibin B and AMH are less useful in predicting ovarian response in a subsequent ART-cycle than is AMH alone. As a result of the low specificity for AMH alone, the age-related high heterogeneity between the normal and poor responder group, and probably an effect of dose adjustment during COH in this study, the correct overall prediction rate for poor response during COH only reaches 36%. If groups are of comparable age, specificity increases to 62% and a correct prediction of poor response will be possible in 88% of the COHs. Sensitivity and prediction of normal response with AMH alone are much more robust and remain unchanged even if there is a high age-related heterogeneity. Levels of AMH <0.5 ng/ml robustly predicted very poor response (≤2 oocytes retrieved) with impaired IVF success.

The antral follicle count is still regarded as a relatively good marker to predict poor ovarian response in ART programs providing better information than the patient's age alone or several endocrine markers (Scheffer et al., 2003Go). However, in our routine clinical setting, we found a high inter-observer variability of antral follicle count due to the duration of the vaginal ultrasound examination, observers experience and, notably, expected ovarian reserve due to patient's age. We therefore excluded the ‘first line antral follicle count’ from further analysis and focused on objectively assessed endocrine markers avoiding observer related variability. Although we found a strong correlation of AMH levels and subsequent ovarian response in ART-cycles by using the cut-off level of AMH ≤1.26 ng/ml, we only have a correct prediction rate of 36%. By using groups of comparable age, the specificity and ‘correct prediction rate of poor response’ will increase significantly, although sensitivity and ‘correct prediction rate of normal response’ are much more robust and will remain unchanged whether or not a high age-related heterogeneity is given. Therefore, AMH measurement and a subsequent antral follicle count should be combined in unselected groups of patients, typical for a clinical setting, to minimize false positive results, as has also been proposed by others previously (Muttukrishna et al., 2005Go; Tremellen et al., 2005Go). But the antral follicle count should be performed accurately as a confirmatory test only in the second line and not as a screening method.

According to the current literature, existing assessments of ovarian reserve have limited predictive properties especially for the occurrence of pregnancy (Broekmans et al., 2006Go). Newest investigations see AMH as a superior predictor of IVF success (live birth rate) (Nelson et al., 2007Go) which cannot be supported by our findings. In our study, AMH and the other examined markers were not predictive for the success of the subsequent IVF treatment, confirming the results of others (van Rooij et al., 2006Go). However, a case wise analysis of all IVF treatments in this study revealed that in all cases with an AMH ≤1.26 ng/ml, a dose adjustment after 5 days of gonadotrophin stimulation was necessary. In this way, we could obviously increase the number of retrieved oocytes and improve treatment outcome. This bias may also explain the low correct prediction rates for poor response in the ‘AMH only’ analysis (Table I).

Recent studies have shown that a low response to gonadotrophin stimulation is associated with early menopause (Nikolaou et al., 2002Go; Lawson et al., 2003Go). AMH also seems to be a promising candidate for the occurrence of menopausal transition (van Rooij et al., 2004Go). Our results show that AMH levels ≤1.26 ng/ml are strongly indicative of significantly diminished ovarian reserve and AMH levels <0.5 ng/ml robustly and correctly predict a very low response (≤2 oocytes) in 88% of cases, supporting the value of AMH as an early warning test for exhausted ovarian function when FSH levels are still within the normal range (Feyereisen et al., 2006Go). The low correlation of inhibin B with poor ovarian response as well as with the success of a subsequent IVF treatment may be explained by the fact that inhibin B not only represents the number of antral follicles, but is closely related to functional changes of the follicles during the cycle and with advancing age (Knight and Glister, 2006Go).

Concluding from our results, we now use AMH as a reliable pre-warning and screening marker for reduced ovarian reserve in women as previously suggested by others (van Rooij et al., 2005Go). In consideration of our results, we generally adapted our treatment strategies for all patients from 30 June 2006 onwards. Regardless of age, women with an AMH >1.26 ng/ml receive a starting dose of 150 mU/ml recombinant FSH or HMG. Patients with an AMH <0.5 ng/ml are started with 375 mU/ml recombinant FSH or HMG and counseled about their impaired prognosis, independently of age. In cases of AMH levels ≥0.5 ng/ml and ≤1.26 ng/ml, the start dosage is fixed to 300 mU/ml recombinant FSH or HMG if an antral follicle count showed <5 follicles/ovary (Kline et al., 2005Go). Women with an AMH ≤0.1 ng/ml are treated only in exceptional cases (trial stimulation) and seriously informed about their bad prognosis (Meduri et al., 2007Go) and the probably cost-ineffective stimulation. Women with an AMH >6 ng/ml are at risk of polyfollicular development and ovarian hyperstimulation (Pigny et al., 2003Go, 2006Go) and are therefore started prudently with 100 mU/ml recombinant FSH. Future studies will be analyzed to see if a further decrease in cycle cancellation rate because of impending hyperstimulation or insufficient ovarian response to gonadotrophin stimulation is possible although in the latter case, past studies have shown disappointing results (Klinkert et al., 2005Go).

In summary, our results confirm the relevance of AMH measurement as an important screening test for reduced ovarian reserve in women. Using AMH alone with a cut-off level ≤1.26 ng/ml, we will identify 97% of all women with a reduced ovarian reserve and correctly predict low response to gonadotrophin stimulation in 88% of cases in groups of comparable age. Furthermore, a level of AMH <0.5 ng/ml correctly predicts very poor response with ≤2 oocytes in 88% of cases and poor outcome even in groups of high age-related heterogeneity. If AMH levels are ≥0.5 ng/ml and ≤1.26 ng/ml, an antral follicle count should be added to exclude false positive results and increase specificity especially in a routine clinical setting with heterogeneous groups of patients.

Chronological age fairly well predicts ovarian response, upcoming perimenopausal and menopausal transition. Important studies have shown that AMH is a predictor for the occurrence of perimenopausal transition (cycle length irregularity) within 3–5 years (de Vet et al., 2002Go; van Rooij et al., 2004Go) at levels <0.92 ng/ml. Our results show that by early detection of women with a reduced ovarian response, using a cut-off level ≤1.26 ng/ml, treatment options are still available (high-dose stimulation in IVF, polyovulation) with favorable pregnancy rates, not statistically different from those women with ‘normal’ ovarian reserve. Therefore, females should be advised to get AMH levels determined if they do not achieve pregnancy after six cycles of regular intercourse (Gnoth et al., 2005Go). AMH is suitable as a screening test and may replace FSH which gains relevance only in the late reproductive phase.


   Funding
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 Funding
Acknowledgements
 References
 
Small grant for statistical analysis (software adaption) by Diagnostic System Laboratories, Inc./Beckman-Coulter, Germany.


   Acknowledgements
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 Funding
 Acknowledgements
References
 
The authors wish to thank Mrs Silvia Heil for recording and preparing the row data and Mrs Andreja Daniels, Mrs Claudia Hammelstein and Mrs Claudia Monissen for all her efforts performing the laboratory essays.

Conflict of interest: The first author was supported by small grant for statistical analysis (software adaptation) by Diagnostic System Laboratories, Inc./Beckman-Coulter, Germany.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 Funding
 Acknowledgements
 References
 
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Submitted on August 21, 2007; resubmitted on March 3, 2008; accepted on March 12, 2008.


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