Newsletter

Table of Contents

02.10.2008

Newsletter No. 5/2008

Anti-mullerian hormone and inhibin B in the definition of ovarian aging and the menopause transition.
The search for genes contributing to endometriosis risk.
Limited value of morphological assessment at days 1 and 2 to predict blastocyst development potential: a prospective study based on 4042 embryos.
Tenascin is highly expressed in endometriosis and its expression is upregulated by estrogen.

1. Anti-mullerian hormone and inhibin B in the definition of ovarian aging and the menopause transition.

CONTEXT/OBJECTIVE: The objective of the study was to determine whether anti-Mullerian hormone (AMH) and inhibin B are viable endocrine biomarkers for framing the menopause transition from initiation to the final menstrual period (FMP). DESIGN: We assayed AMH, inhibin B, and FSH in 300 archival follicular phase specimens from 50 women with six consecutive annual visits commencing in 1993 when all women were in the pre- and perimenopausal menopause stages. Subsequently each woman had a documented FMP. The assay results were fitted as individual-woman profiles and then related to time to FMP and age at FMP as outcomes. RESULTS: Based on annual values from six time points prior to the FMP, (log)AMH longitudinal profiles declined and were highly associated with a time point 5 yr prior to FMP [including both observed and values below detection (P < 0.0001 and P = 0.0001, respectively)]. Baseline AMH profiles were also associated with age at FMP (P = 0.035). Models of declining (log)inhibin B profiles (including both observed and values below detection) were associated with time to FMP (P < 0.0001 and P = 0.0003, respectively). There was no significant association of (log)inhibin B profiles with age at FMP. CONCLUSIONS: AMH, an endocrine marker that reflects the transition of resting primordial follicles to growing follicles, declined to a time point 5 yr prior to the FMP; this may represent a critical biological juncture in the menopause transition. Low and nondetectable levels inhibin B levels also were observed 4-5 yr prior to the FMP but were less predictive of time to FMP or age at FMP.

Sowers MR, Eyvazzadeh AD, McConnell D, Yosef M, Jannausch ML, Zhang D, Harlow S, Randolph JF Jr. Anti-mullerian hormone and inhibin B in the definition of ovarian aging and the menopause transition, J Clin Endocrinol Metab. 2008 Sep;93(9):3478-83

2. The search for genes contributing to endometriosis risk.

BACKGROUND: Genetic variation contributes to the risk of developing endometriosis. This review summarizes gene mapping studies in endometriosis and the prospects of finding gene pathways contributing to disease using the latest genome-wide strategies. METHODS: To identify candidate-gene association studies of endometriosis, a systematic literature search was conducted in PubMed of publications up to 1 April 2008, using the search terms "endometriosis" plus "allele" or "polymorphism" or "gene". Papers included were those with information on both case and control selection, showed allelic and/or genotypic results for named germ-line polymorphisms and were published in the English language. RESULTS: Genetic variants in 76 genes have been examined for association, but none shows convincing evidence of replication in multiple studies. There is evidence for genetic linkage to chromosomes 7 and 10, but the genes (or variants) in these regions contributing to disease risk have yet to be identified. Genome-wide association is a powerful method that has been successful in locating genetic variants contributing to a range of common diseases. Several groups are planning these studies in endometriosis. For this to be successful, the endometriosis research community must work together to genotype sufficient cases, using clearly defined disease classifications, and conduct the necessary replication studies in several thousands of cases and controls. CONCLUSIONS: Genes with convincing evidence for association with endometriosis are likely to be identified in large genome-wide studies. This will provide a starting point for functional and biological studies to develop better diagnosis and treatment for this debilitating disease.

Montgomery GW, Nyholt DR, Zhao ZZ, Treloar SA, Painter JN, Missmer SA, Kennedy SH, Zondervan KT. The search for genes contributing to endometriosis risk.Hum Reprod Update. 2008 Sep-Oct;14(5):447-57.

3. Limited value of morphological assessment at days 1 and 2 to predict blastocyst development potential: a prospective study based on 4042 embryos.

BACKGROUND: Non-invasive and routine developmental markers are available to select the most viable embryo; however their respective values in terms of blastocyst development potential remain difficult to distinguish. METHODS: During this prospective study, the sequential growth of 4042 embryos individually cultured from day 1 to day 5/6 was recorded. Pronuclear morphology on day 1, and early cleavage, cell number and fragmentation rate on day 2 were evaluated for each zygote. Additionally, blastocyst transfers were analysed with regard to their implantation ability and early embryo development parameters. RESULTS: Once adjusted to each other, each of the four parameters remained related to blastocyst development. Early cleavage and cell number on day 2 were the most powerful parameters to predict the development of a good morphology blastocyst at day 5. Moreover, whereas transfers of a good morphology blastocyst were associated with high implantation and live birth rates, parameters of early development were not helpful in predicting their implantation ability. CONCLUSIONS: The combination of all four parameters allowed the prediction of blastocyst development with an area under the receiver operating characteristics curve of 0.688, which represents a fairly low prediction of embryo viability. Such results indicate that it is necessary to search for additional criteria, including the ability of the blastocyst to develop.

Guerif F, Le Gouge A, Giraudeau B, Poindron J, Bidault R, Gasnier O, Royere D. Limited value of morphological assessment at days 1 and 2 to predict blastocyst development potential: a prospective study based on 4042 embryos. Hum Reprod. 2007 Jul;22(7):1973-81.

4. Tenascin is highly expressed in endometriosis and its expression is upregulated by estrogen.

OBJECTIVE: To investigate the localization of tenascin expression in the endometrium of women without endometriosis and in endometriotic implants, and to determine the in vitro regulation of tenascin by E(2) in these tissues. DESIGN: Experimental laboratory study. SETTING: University medical center. PATIENT(S): Reproductive age women with or without endometriosis. INTERVENTION(S): Proliferative (n = 14), and secretory (n = 14) endometrium from women without endometriosis and endometriosis implants (n = 14) were used for immunohistochemical analysis. Endometrial and endometriotic stromal cells were grown in culture and treated with E(2), the estrogen receptor antagonist ICI 182 780 (ICI) alone, E(2) in combination with ICI, or vehicle (control) for 24 hours, and tenascin expression was analyzed by Western blotting. MAIN OUTCOME MEASURE(S): Expression levels of tenascin in normal endometrium and endometriotic implants and its regulation by E(2). RESULT(S): Tenascin immunostaining revealed an increasing intensity in the stromal cells, starting from normal secretory endometrium, then normal proliferative endometrium, and reaching the highest expression in endometriotic implants. Estradiol induced a significant increase in tenascin protein levels in the endometriotic stromal cells in culture. CONCLUSION(S): The modulation of tenascin as an extracellular matrix protein by E(2) in endometriotic stromal cells may be one of the factors playing a role in the development of endometriosis.

Tan O, Ornek T, Seval Y, Sati L, Arici A. Tenascin is highly expressed in endometriosis and its expression is upregulated by estrogen. Fertil Steril. 2008 May;89(5):1082-9. Epub 2007 Aug 6.

Gerhard Leyendecker