Response to editorial entitled “Biomarkers of endometrial receptivity through a minimally invasive approach”

30 05 2013

To the Editor:

The editorial by Dr. Robert Norman in this issue of Fertility and Sterility (1) succinctly summarizes the various approaches currently used to identify biomarkers of endometrial receptivity toward development of a viable predictive/assessment test for clinical application. As Dr. Norman points out, multiple approaches have been applied to identify candidate biomarkers, including proteomic and lipidomic assessments of uterine aspirate fluid and gene expression profiling of endometrial biopsies. In this editorial, Dr. Norman introduces our paper in which we demonstrate the feasibility of performing genome-wide gene expression profiling on uterine aspirations (2). Using unsupervised hierarchical clustering, we demonstrate that the phase of sampling (LH+2 versus LH+7) affects gene expression more so than individual differences in gene expression between patients. We identified and verified robust differences in expression of 245 genes due to phase of sampling and determined that expression of 53 of these genes efficiently separated our two groups and those of a publically available dataset of gene expression signatures obtained from endometrial biopsy samples. Since LH+2 coincides with a pre-receptive phase and LH+7 coincides with a receptive phase in fertile women, the differentially expressed genes identified in our study encode for candidate biomarkers of endometrial receptivity. This 53-gene list overlaps significantly with those indicated in other studies, including the 238-gene list comprising the endometrial receptivity assay used by Diaz-Gimeno et al. (3) in their algorithm for predicting the receptive period from endometrial biopsy samples. We are excited by the potential of our approach because uterine aspiration is less traumatic to the endometrium than biopsy. Unlike endometrial biopsy, uterine aspiration is compatible with evaluation within an active IVF or natural cycle in which a patient is attempting pregnancy (4, 5), enabling us and other researchers to directly associate altered gene expression with implantation success. This approach will facilitate our future identification of those candidate biomarkers for further development of point-of-care assays for clinical use. While our 53-gene cassette includes several interesting candidate biomarkers, including those encoding secreted products, we do not propose these as a clinical test. Rather, we propose that our approach enables further testing and reduction of this signature to identify those genes most predictive. We agree with Dr. Norman that protein-based assays will be preferable to transcript measurements for clinical assays; however, gene expression data are necessary to direct proteomic discovery assays to improve these approaches. Read the rest of this entry »

Whatever its variability, AMH remains the most stable hormonal predictor

8 04 2013

To the Editor:

Dr. Hadlow and colleagues argue that antimüllerian hormone (AMH) levels decrease in the luteal phase and that the hormone should be measured in the follicular phase, since this variability may lead to misprediction of ovarian response in IVF. This assumption was made on the basis of few, not frequent, blood samples performed on a very limited sample of women (1).

In the study, the intra-individual variability of AMH was found to be similar to that of FSH. This finding is really surprising and points out a critical revision of the results obtained. Both of the largest available studies to date (2, 3) reported that 89% of the variation in AMH was due to between-subjects variation, while only 11% was due to true individual fluctuations. AMH may exhibit some variability, but the important point is that the fluctuations are randomly distributed throughout the menstrual cycle (4), raising the possibility that a fixed day for its measurement, as proposed, would be useless. The suggested cyclic moifications of AMH in Dr. Hadlow’s study need to be confirmed in studies investigating hormonal variability through more frequent samples and across at least two menstrual cycles. A logical and agreeable hypothesis explaining why AMH should reduce in the luteal phase needed to be formulated by the authors. If AMH is produced by antral follicles, the number of which shows no significant reduction in the luteal phase, and since AMH seems to be only marginally influenced by gonadotropins, why should its concentration reduce in the second part of the cycle? Read the rest of this entry »

Luteinizing hormone surge in normally ovulating women

21 01 2013

To the Editor:

After reading the article “Relationships between the luteinizing hormone surge and other characteristics of the menstrual cycle in normally ovulating women” (1), now including concurrent ultrasound data I would like to confirm once more hormonal findings published in Fertility and Sterility more than a decade ago (2). Unnoticed, Park et al. also described these LH patterns in your journal in 2007 (3).

I have reanalyzed the data published originally (2), according to the methods specified in the studies by Direito et al. and Park et al. (1, 3), and shown data from all three studies in Tables 1 and 2. The sum (25%) of what was first described as two peaks and a small peak (2) would be comparable herein to a double peak. Park et al. found a luteinizing hormone (LH) surge of rapid onset (within 1 day) in 42.9% of patients, and of gradual onset (in 2 to 6 days) in 57.1%, or 25.6% and 74.4% in 2 to 10 days, respectively. Overall, although in some cases there seemed to be a tendency, after analyzing three or more cycles from each woman, I did not clearly find repetition of the same type of LH profile within the same woman reported by Direito et al. Relating LH and Pregnanediol Glucuronide (PDG) profiles, a novel finding is that cases with double- and multiple-peaked LH surges associated significantly with transient rises in PDG before the definite rise (P<0.001, Chi test; PDG rise according to Park et al.). Read the rest of this entry »

Are Chinese people really more fertile?

5 05 2010

To the Editor:

We congratulate Bilian et al. on an important contribution to the research informing day-specific probabilities of conception (1). However, we question their conclusion of an ethnic difference in fecundity. Over half of their female participants had a previous pregnancy (Table 1), and all of the men had clinically proven fertility, which selected for couples of substantially higher fecundity than the participants in the North Carolina Early Pregnancy Study (2). Read the rest of this entry »