Dorothea Wunder

Age-related normograms of serum antimüllerian hormone levels in a population of infertile women: a multicenter study

OBJECTIVE To produce age-related normograms for serum antimüllerian hormone (AMH) level in infertile women without polycystic ovaries (non-PCO). DESIGN Retrospective cohort analysis. SETTING Fifteen academic reproductive centers. PATIENT(S) A total of 3,871 infertile women. INTERVENTION(S) Blood sampling for AMH level. MAIN OUTCOME MEASURE(S) Serum AMH levels and correlation between age and different percentiles of AMH. RESULT(S) Age-related normograms for the 3rd, 10th, 25th, 50th, 75th, 90th, and 97th percentiles of AMH were produced. We found that the curves of AMH by age for the 3rd to 50th percentiles fit the model and appearance of linear relation, whereas the curves of >75th percentiles fit cubic relation. There were significant differences in AMH and FSH levels and in antral follicle count (AFC) among women aged 24-33 years, 34-38 years, and ≥39 years. Multivariate stepwise linear regression analysis of FSH, age, AFC, and the type of AMH kit as predictors of AMH level shows that all variables are independently associated with AMH level, in the following order: AFC, FSH, type of AMH kit, and age. CONCLUSION(S) Age-related normograms in non-PCO infertile women for the 3rd to 97th percentiles were produced. These normograms could provide a reference guide for the clinician to consult women with infertility. However, future validation with longitudinal data is still needed.

Pregnancy and reproduction in autoimmune rheumatic diseases

Despite evidence for the important role of oestrogens in the aetiology and pathophysiology of chronic immune/inflammatory diseases, the previous view of an unequivocal beneficial effect of oestrogens on RA compared with a detrimental effect on SLE has to be reconsidered. Likewise, the long-held belief that RA remits in the majority of pregnant patients has been challenged, and shows that only half of the patients experience significant improvement when objective disease activity measurements are applied. Pregnancies in patients with SLE are mostly successful when well planned and monitored interdisciplinarily, whereas a small proportion of women with APS still have adverse pregnancy outcomes in spite of the standard treatment. New prospective studies indicate better outcomes for pregnancies in women with rare diseases such as SSc and vasculitis. Fertility problems are not uncommon in patients with rheumatic disease and need to be considered in both genders. Necessary therapy, shortly before or during the pregnancy, demands taking into account the health of both mother and fetus. Long-term effects of drugs on offspring exposed in utero or during lactation is a new area under study as well as late effects of maternal rheumatic disease on children.

Anti-Müllerian hormone and inhibin B as predictors of pregnancy after treatment by in vitro fertilization/intracytoplasmic sperm injection

OBJECTIVE To evaluate anti-Müllerian hormone (AMH) as a marker of reproductive outcome after IVF/intracytoplasmic sperm injection (ICSI). DESIGN Longitudinal study. SETTING University hospital. PATIENT(S) Two hundred seventy-six consecutive women undergoing IVF/ICSI. INTERVENTION(S) Ovarian stimulation, oocyte retrieval, IVF, ICSI, embryo transfer, AMH, and inhibin B determinations in serum and follicular fluid (FF). MAIN OUTCOME MEASURE(S) The AMH and inhibin B concentrations in 276 matched FF/serum pairs have been determined. Different outcome groups have been compared and set in relation to the oocyte count, morphological parameters, and steroid hormone levels. RESULT(S) The concentrations of AMH and inhibin B in both serum and FF were significantly higher in the group of women who became pregnant in the corresponding treatment cycle than in those who did not conceive. Positive correlations were observed between serum inhibin B concentrations and embryo morphology (r = 0.126, 95% confidence interval 0.026-0.284). Serum and FF AMH or inhibin B correlated positively with the oocyte count and negatively with the pretreatment cycle day 3 FSH level and the total administered gonadotropin dose. CONCLUSION(S) The AMH and inhibin B levels on the day of oocyte retrieval are correlated to reproductive outcome.

The expression of estrogen receptors as well as GREB1, c-MYC, and cyclin D1, estrogen-regulated genes implicated in proliferation, is increased in peritoneal endometriosis

OBJECTIVE To analyze the expression of estrogen receptors α and β as well as their target genes implicated in proliferation, c-myc, cyclin D1, and GREB1, in the endometrium of women with or without endometriosis. DESIGN Expression analysis in human tissue. SETTING University hospitals and a clinic. PATIENT(S) Ninety-one premenopausal women (59 patients with endometriosis and 32 controls) undergoing laparoscopic surgery. INTERVENTION(S) Biopsies were obtained at time of surgery, performed during the proliferative phase of the cycle. MAIN OUTCOME MEASURE(S) Estrogen receptors α and β as well as c-myc, cyclin D1, and GREB1 mRNA expression levels were determined by quantitative reverse transcriptase-polymerase chain reaction. Tissue localization of these estrogen-regulated genes was analyzed by immunohistochemistry. RESULT(S) Estrogen receptors α and β as well as c-myc, cyclin D1, and GREB1 mRNA expression levels were increased in ectopic tissue in comparison with both normal and eutopic endometrium. Estrogen receptor mRNA levels also were upregulated in the eutopic peritoneal tissue of patients with endometriosis. Cyclin D1 and GREB1 expression was augmented in eutopic endometrium. c-myc, cyclin D1, and GREB1 proteins exhibited a nuclear localization in ectopic endometrial tissue. CONCLUSION(S) This constitutes the first report of increased expression of GREB1, as well as cyclin D1 and c-myc, in peritoneal endometriotic lesions, implicating these proteins in estrogen-dependent growth in this context.

Increased ENA-78 in the follicular fluid of patients with endometriosis

Background. It is known that endometriosis is an inflammatory disease and those patients seem to have lower pregnancy rates. The aim of the study was to investigate the concentrations of chemokines and proinflammatory cytokines in the follicular fluid of patients with and without endometriosis. Methods. Follicular aspiration, recovering follicular fluid during assisted reproductive treatment, follicular fluid storage and analysis of chemokines and proinflammatory cytokines were carried out. Tumor necrosis factor‐α, interleukin‐1β, interleukin‐6, interleukin‐8, interleukin‐15, leukemia inhibitory factor, epithelial neutrophil‐activating peptide 78, regulated upon activation, normal T‐cell expressed and secreted, and growth‐regulated oncogene‐α were analyzed in the follicular fluid and compared between women with (n=47) and without endometriosis (n=279). Results. The above cytokines were detected in the follicular fluid samples. Epithelial neutrophil‐activating peptide 78 levels were significantly higher in follicular fluid from endometriosis patients than from controls (p=0.008). Increases (to twice the control level) were also observed for tumor necrosis factor‐α and for interleukin‐6. Conclusions. Increased follicular fluid levels of epithelial neutrophil‐activating peptide 78, tumor necrosis factor‐α and interleukin‐6 indicate that these cytokines may influence oocyte quality and fecundability of women with endometriosis by deteriorating the microenvironment in the human follicle.

Adiponectin as a marker of success in intracytoplasmic sperm injection/embryo transfer cycles

Adiponectin (Acrp30) is an adipose tissue-derived protein whose serum concentrations, in contrast to leptin, are reported to be negatively correlated to body mass. In spite of the comparatively high circulating adiponectin concentrations, this protein has not been studied in the context of assisted reproduction to date. The aim of this preliminary project was thus to examine the potential of adiponectin to serve as a marker for fertility. We compared adiponectin levels in serum before and after controlled ovarian hyperstimulation, as well as in follicular fluid (FF), between two groups: those with successful outcome (clinical pregnancies) and those with implantation failure. In the former, adiponectin concentrations were higher than in the negative outcome group; this difference was statistically significant (p < 0.05) in serum on the day of oocyte pick-up (OPU) as well as two or three days before OPU, but not in FF or in serum at the beginning of the stimulation phase. This finding adds a new perspective to the suggested but still controversial reduction in FF leptin concentrations in the positive outcome group, and may become a useful tool for early prediction of success of in vitro fertilization treatment for a given patient.

Steroids and protein markers in the follicular fluid as indicators of oocyte quality in patients with and without endometriosis

Purpose: To investigate the concentrations of steroid hormones (estradiol, progesterone), pregnancy–associated protein-A, IGF-binding protein-4 and leptin in the follicular fluid of infertile patients with and without endometriosis.Methods: Follicular fluid of IVF patients with and without endometriosis was aspirated, centrifuged and stored to analyze the above mentioned hormones and to compare their concentrations between women with and without endometriosis.Results: Follicular fluid estradiol levels were significantly higher in controls than in affected women. The concentrations of the other markers did not differ between the two groups.Conclusions: Since not only the follicular fluid concentration of estradiol, but also the oocyte quality is decreased in women with endometriosis, we suggest that estradiol can be considered as a marker not only of oocyte maturity but also of oocyte quality.

Gene expression in cultured endometrium from women with different outcomes following IVF

Estradiol and progesterone are crucial for the acquisition of receptivity and the change in transcriptional activity of target genes in the implantation window. The aim of this study was to differentiate the regulation of genes in the endometrium of patients with recurrent implantation failure (IF) versus those who became pregnant after in vitro fertilization (IVF) treatment. Moreover, the effect of embryo-derived factors on endometrial transcriptional activity was studied. Nine women with known IVF outcome (IF, M, miscarriage, OP, ongoing pregnancy) and undergoing hysteroscopy with endometrial biopsy were enrolled. Biopsies were taken during the midluteal phase. After culture in the presence of embryo-conditioned IVF media, total RNA was extracted and submitted to reverse transcription, target cDNA synthesis, biotin labelling, fragmentation and hybridization using the Affymetrix Human Genome U133A 2.0 Chip. Differential expression of selected genes was re-analysed by quantitative PCR, in which the results were calculated as threshold cycle differences between the groups and normalized to Glyceraldehyde phosphate dehydrogenase and beta-actin. Differences were seen for several genes from endometrial tissue between the IF and the pregnancy groups, and when comparing OP with M, 1875 up- and 1807 down-regulated genes were returned. Real-time PCR analysis confirmed up-regulation for somatostatin, PLAP-2, mucin 4 and CD163, and down-regulation of glycodelin, IL-24, CD69, leukaemia inhibitory factor and prolactin receptor between Op and M. When the different embryo-conditioned media were compared, no significant differential regulation could be demonstrated. Although microarray profiling may currently not be sensitive enough for studying the effects of embryo-derived factors on the endometrium, the observed differences in gene expression between M and OP suggest that it will become an interesting tool for the identification of fertility-relevant markers produced by the endometrium.

Frequency of Gynecologic Follow-Up and Cervical Cancer Screening in the Swiss HIV Cohort Study

Background:According to current recommendations, HIV-infected women should have at least 1 gynecologic examination per year. Objectives:To analyze factors associated with frequency of gynecologic follow-up and cervical cancer screening among HIV-infected women followed in the Swiss HIV Cohort Study (SHCS). Methods:Half-yearly questionnaires between April 2001 and December 2004. At every follow-up visit, the women were asked if they had had a gynecologic examination and a cervical smear since their last visit. Longitudinal models were fitted with these variables as outcomes. Results:A total of 2186 women were included in the analysis. Of the 1146 women with complete follow-up in the SHCS, 35.3% had a gynecologic examination in each time period, whereas 7.4% had never gone to a gynecologist. Factors associated with a poor gynecologic follow-up were older age, nonwhite ethnicity, less education, underweight, obesity, being sexually inactive, intravenous drug use, smoking, having a private infectious disease specialist as a care provider, HIV viral load <400 copies/mL, and no previous cervical dysplasia. No association was seen for living alone, CD4 cell count, and positive serology for syphilis. Conclusions:Gynecologic care among well-followed HIV-positive women is poor and needs to be improved.

Antiretroviral treatment during pregnancy

Objective: Virologic failure of HIV-positive patients is of special concern during pregnancy. We compared virologic failure and the frequency of treatment changes in pregnant and non-pregnant women of the Swiss HIV Cohort Study. Methods: Using data on 372 pregnancies in 324 women we describe antiretroviral therapy during pregnancy. Pregnant women on HAART at conception (n = 131) were matched to 228 non-pregnant women (interindividual comparison) and to a time period of equal length before and after pregnancy (intraindividual comparison). Women starting HAART during pregnancy (n = 145) were compared with 578 non-pregnant women starting HAART. Findings: The median age at conception was 31 years, 16% (n = 50) were infected through injecting drug use and the median CD4 cell count was 489 cells/μl. In the majority of pregnancies (n = 220, 59%), women had started ART before conception. When ART was started during pregnancy (n = 145, 39%), it was mainly during the second trimester (n = 100, 69%). Two thirds (n = 26) of 35 women starting in the third trimester were diagnosed with HIV during pregnancy. The risk of virologic failure tended to be lower in pregnant than in non-pregnant women [adjusted odds ratio 0.52 (95% confidence interval 0.25–1.09, P = 0.08)], but was similar in the intraindividual comparison (adjusted odds ratio 1.04, 95% confidence interval 0.48–2.28). Women starting HAART during pregnancy changed the treatment less often than non-pregnant women. Conclusion: Despite the physiological changes occurring during pregnancy, HIV infected pregnant women are not at higher risk of virologic failure.