Affiliations of authors: Unidad de Reproducción Humana Asistida, Hospital Universitario Príncipe de Asturias, Alcalá de Henares, Madrid, Spain (FC, LM); Departamento de Genómica Estructural. Neocodex, Sevilla, Spain (FJM, JJG, LMR, AR)
Correspondence to: Agustín Ruiz, MD, PhD, Departamento de Genómica Estructural. Neocodex. Edificio Acrópolis Módulos 110-111, c/Averroes no. 8, 41020-Sevilla, Spain (e-mail: aruiz{at}neocodex.es)
The Journal recently published a study analyzing the role of sequence variation of genes involved in steroid hormone metabolism in the serum sex hormone levels of postmenopausal women (1). This study concluded that CYP19 and SBGH polymorphisms contribute to the variability in circulating sex hormones in postmenopausal women, although CYP19 or SHBG polymorphisms are only marginally related to breast cancer susceptibility. However, after comparing results from a study we recently published (2) with those of Dunning et al. (1), we think that because of the complexity of the genetic control of estrogen production in pre- and postmenopausal women, a multilocus rather than a marker-by-marker statistical analysis may be best suited for the study of the genetic component of complex traits such as hormone levels or breast cancer risk (3). Therefore, we would like to suggest further analysis of the data presented by Dunning et al.
Using a pharmacogenetics approach, we are studying the role of different loci looking at the effect of gonadrotropin releasing hormone agonist (GnRHa) and other hormones during controlled ovarian stimulation (COS) in premenopausal women (2). Hormone-related cancers and assisted reproduction techniques are routine GnRHa indications. GnRHa administration suppresses the estrogen production in the ovary via the biochemical ablation of the hypothalamushypophysisovary axis (pituitary suppression). Pituitary suppression represents a unique pharmacogenetics model to study the function and regulation of the CYP19 aromatase, because only a small proportion of women reach partial estrogen synthesis suppression after GnRHa treatment (4,5). To study the association of different genetic polymorphisms with pituitary suppression caused by GnRHa treatment, 213 premenopausal women were treated with GnRHa tryptorelin, as previously reported (2). Patients were grouped according to degree of pituitary suppression and genotyped for several loci (2). Table 1 summarizes the results of our study using four single-nucleotide polymorphism (SNP) markers located at FSHR, CYP19, ESR1, and ESR2. Twenty-four percent of the patients responded only partially to GnRHa treatment. In addition, our results suggest that the rs10046 marker of the CYP19 locus is associated with pituitary suppression in premenopausal women (Pallele positivity test for risk allele c <.001). These results are also consistent with quantitative analysis that showed a higher mean number of days to reach pituitary suppression in women who carry the cc genotype than the tt genotype at the rs10046 locus (KruskallWallis statistic = 6.86; P = .0088). Finally, following a conservative multi-locus analysis (2), a genetic interaction between CYP19, ESR1, and ESR2 loci and pituitary suppression was detected (P = .0199), suggesting that pituitary suppression could be a polygenic trait.
|
NOTES
We are deeply grateful to the patients for their participation in this study. This study has been supported by the European Commission (QLK4-CT-200202403) and by the Ministerio de Ciencia y Tecnología of Spain (FIT010000200468, PTQ-20020206, and PTQ-2000546).
REFERENCES
1 Dunning AM, Dowsett M, Healey CS, Tee L, Luben RN, Folkerd E et al. Polymorphisms associated with circulating sex hormone levels in postmenopausal women. J Natl Cancer Inst 2004;96:936945.
2 de Castro F, Moron FJ, Montoro L, Galan JJ, Hernandez DP, Padilla ES et al. Human controlled ovarian hyperstimulation outcome is a polygenic trait. Pharmacogenetics 2004;14:28593.[CrossRef][ISI][Medline]
3 Hoh J, Ott J. Mathematical multi-locus approaches to localizing complex human trait genes. Nat Rev Genet 2003;4:7019.[ISI][Medline]
4 Wikland M, Borg J, Hamberger L, Svalander P. Simplification of IVF: minimal monitoring and the use of subcutaneous highly purified FSH administration for ovulation induction. Hum Reprod 1994;9:14306.[Abstract]
5 Child TJ, Sylvestre C, Tan SL. Endometrial volume and thickness measurements predict pituitary suppression and non-suppression during IVF. Hum Reprod 2002;17:31103.
6 Simpson ER. Sources of estrogen and their importance. J Steroid Biochem Mol Biol 2003;86:22530.[CrossRef][ISI][Medline]
7 Simpson ER. Aromatase: biologic relevance of tissue-specific expression. Semin Reprod Med 2004;22:1123.[CrossRef][ISI][Medline]
Response to this Correspondence
![]() |
||||
|
Oxford University Press Privacy Policy and Legal Statement |