Endometriosis and oxidative stress—serum markers?

designs like cross-sectional, case-control, or cohort studies. The beauty of the clinical trial is that, because of the random allocation of treatment, the groups will be asymptotically balanced with regard to all factors, both measured and unmeasured. That is to say, given adequate sample size, the distribution of all important factors will be equivalent by group and the potential for confounding effectively addressed. Unfortunately, many trials are small enough that important group differences may arise simply due to chance. When investigators anticipate small sample size for a trial and the presence of important predictors of the outcome of interest may become unbalanced, blocking is an effective way to ensure equal distributions of those factors in the groups. In block randomized trials, investigators randomize treatment within strata of such factors to assure that these factors are balanced in the treatment arms. Treatment allocation remains random—the key facet of randomized trials in regard to inference—although the distribution of matching factors becomes distorted from what might otherwise occur in the population. Seen in this light, it is clear that blocked randomized trials are indeed ‘‘true’’ in all important senses, and are thus reasonably considered as such. The study in question (2) created blocks of patients with equal age, stimulation protocol, and number of embryos transferred, and then randomly assigned to treatment within these blocks. As can be seen in the Cochrane Handbook guidelines for selecting studies for inclusion in reviews (3), inclusion of the study in question (2) is quite in line with the current thinking regarding evidence-based medicine and meta-analysis noted by Mijatovic and colleagues. An important conclusion we previously made (1) is highlighted by this discussion—the sensitivity of results to a single (set of) data point(s). We reiterate our statements regarding the inadequacy of data to be used for achieving a clear consensus on the question of interest. Given this degree of uncertainty, the jury must remain out on this scientific question until further evidence can help guide decision making. Brian W. Whitcomb, Ph.D. Enrique F. Schisterman, Ph.D. Marcus D. Ruopp, B.A. Tara C. Collins, M.D. Division of Epidemiology, Statistics and Prevention Research National Institute of Child Health and Human Development National Institutes of Health Department of Health and Human Services Bethesda, Maryland February 25, 2008

REFERENCES 1. Ruopp MD, Collins TC, Whitcomb BW, Schisterman EF. Evidence of absence or absence of evidence? A reanalysis of the effects of low-dose aspirin in in vitro fertilization. Fertil Steril. Published online September 24, 2007 [Epub ahead of print].

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2. Check JH, Dietterich C, Lurie D, Nazari A, Chuong J. A matched study to determine whether low-dose aspirin without heparin improves pregnancy rates following frozen embryo transfer and/or affects endometrial sonographic parameters. J Assist Reprod Genet 1998;15:579–82. 3. Higgins JPT, Green S, eds. Section 5. Locating and selecting studies for reviews. In: Cochrane Handbook for Systematic Reviews of Interventions 4.2.5. Chichester, UK: John Wiley & Sons, updated May 2005.

doi:10.1016/j.fertnstert.2008.02.156

Endometriosis and oxidative stress—serum markers? To the Editor: We read with interest the article of Lambrinoudaki et al. (1), who concluded that women with a history of arterial hypertension had higher mean ischemia modified albumin (IMA) levels compared with women with normal blood pressure, independently of the presence of endometriosis. To further elucidate the relationship between hypertensive pregnancy and oxidative stress, we evaluated IMA in 14 preeclamptic women, 7 with mild preeclampsia (proteinuria R300 mg/24 h and at least two readings of systolic blood pressure R140 mm Hg and diastolic blood pressure R90 mm Hg), and 7 women with severe preeclampsia (proteinuria R300 mg/24 h and at least two readings of systolic blood pressure R160 mm Hg and diastolic blood pressure R110 mm Hg), compared to 39 normotensive pregnant women, matched for age and ethnic origin. In our investigation, significant differences in IMA values were observed between preeclamptic and normotensive women (110.9  7 vs. 102.8  7.1 kunits/L, P¼.009). In preeclampsia, oxidative stress, induced by placental ischemia and reperfusion (2), is considered one of the factors in the disease process (3), which has prompted Lambrinoudaki et al. to hypothesize an increase of systemic oxidative stress in patients with endometriosis (1). Oxidative stress is caused by an imbalance between the production of reactive oxygen and a biological system’s ability to readily detoxify the reactive intermediates or easily repair the resulting damage. Although the definite mechanism for IMA production in vivo is yet unknown, it appears to be related to the generation of reactive oxygen species (ROS) that modify metal binding domains on the albumin moiety (4). There are several conditions that might modify the amino-terminal region of the protein, and therefore the albumin cobalt binding. Cobalt chloride is a well-established chemical inducer of hypoxialike responses, such as erythropoiesis and angiogenesis in vivo, likely involving an increased DNA binding activity of hypoxia-inducible factor-1a (HIF-1a) to its target genomic sequences. Genes modulated by the HIF-1a binding include those encoding for angiogenetic growth factors, cytokines, survival factors, and proapoptotic proteins (5). It has been speculated that cobalt might stabilize HIF-1a through generation of ROS by a nonenzymatic, nonmitochondrial mechanism (6). Therefore, enhanced generation of ROS, reflected by increased IMA levels, could trigger an oxidative Vol. 89, No. 5, May 2008

stress condition, involved in both endometriosis and preeclampsia. Martina Montagnana, M.D.a Giuseppe Lippi, M.D.a Alessandro Albiero, M.D.b Massimo Franchi, M.D.b Cesare Gian Guidi, M.D.a a Sezione di Chimica Clinica, Dipartimento di Patologia, and b Unita` di Ostetricia, Dipartimento Materno ed Infantile Universita` di Verona, Verona, Italy February 4, 2008 REFERENCES 1. Lambrinoudaki IV, Augoulea A, Christodoulakos GE, Economou EV, Kaparos G, Kontoravdis A, et al. Measurable serum markers of oxidative stress response in women with endometriosis. Fertil Steril. Published online January 17, 2008. 2. Sibai B, Dekker G, Kupferminc M. Pre-eclampsia. Lancet 2005;365: 785–99. 3. Patil SB, Kodliwadmath MV, Kodliwadmath SM. Role of lipid peroxidation and enzymatic antioxidants in pregnancy-induced hypertension. Clin Exp Obstet Gynecol 2007;34:239–41. 4. Gidenne S, Ceppa F, Fontan E, Perrier F, Burnat P. Analytical performance of the albumin cobalt binding (ACB) test on the Cobas MIRA Plus analyzer. Clin Chem Lab Med 2004;42:455–61. 5. Dery MA, Michaud MD, Richard DE. Hypoxia-inducible factor-1: regulation by hypoxic and non-hypoxic activators. Int J Biochem Cell Biol 2005;37:535–40. 6. Lippi G, Montagnana M, Guidi GC. Albumin cobalt binding and ischemia modified albumin generation: an endogenous response to ischemia? Int J Cardiol 2006;108:410–1.

doi:10.1016/j.fertnstert.2008.02.151

Reply of the Authors: We would like to thank Dr. Montagnana and her colleagues for their kind comments on our work (1). Ischemia modified albumin (IMA) is a new promising biomarker reflecting myocardial ischemia, which increases early in the process of acute coronary events and may thus contribute to an early and accurate diagnosis (2). Beyond ischemic cardiac events, however, IMA may increase in any condition associated with ischemia. Pregnancy per se is associated with increased circulating IMA levels. First trimester circulating IMA is significantly higher compared to nonpregnant controls, possibly due to ischemia induced by trophoblast development (3). Furthermore, fetal IMA from complicated deliveries is 50% higher compared to uneventful deliveries and may increase by more than 300% in cases of severe fetal hypoxia, serving thus as a biomarker of fetal distress (4). Preeclampsia is a severe obstetric complication posing serious threats to both mother and fetus. We read with great interest the results of Dr. Montagnana and her colleagues showing that preeclamptic women have higher circulating IMA compared to normotensive women. A clinical research protocol is currently in progress in our Department evaluating among other factors Fertility and Sterility

circulating IMA in preeclamptic women stratified by the severity of the hypertensive disease. The aim of the protocol is to identify circulating biomarkers that may serve as early diagnostic tests predicting subsequent development of hypertensive disease in pregnancy. Irene Lambrinoudaki, M.D.a George Kaparos, Ph.D.b Areti Augoulea, M.D.a Emmanuel Economou, Ph.D.b Maria Creatsa, M.D.a Konstantinos Papadias, M.D.a a Second Department of Obstetrics and Gynecology b Hormonal and Biochemical Laboratory University of Athens, Aretaieio Hospital Athens, Greece February 25, 2008 REFERENCES 1. Lambrinoudaki I, Augoulea A, Economou E, Kaparos G, Kontoravdis A, Papadias C, et al. Measurable serum markers of oxidative stress response in women with endometriosis. Fertil Steril. In press. 2. Lippi G, Montagnana M, Salvagno GL, Guidi GC. Potential value for new diagnostic markers in the early recognition of acute coronary syndromes. CJEM 2006;8:27–31. 3. Perfumo F, Gaze DC, Papageorghiou AT, Collinson PO, Thilaganathan B. First trimester maternal serum ischemia-modified albumin: a marker of hypoxia-ischemia-driven early trophoblast development. Hum Reprod 2007;22:2029–32. 4. Gugliucci A, Hermo R, Monroy C, Numaguchi M, Kimura S. Ischemiamodified albumin levels in cord blood: a case-control study in uncomplicated and complicated deliveries. Clin Chim Acta 2005;362:155–60.

doi:10.1016/j.fertnstert.2008.02.152 Successful pregnancy after four-step hysteroscopic technique for the treatment of atypical polypoid adenomyoma To the Editor: We read with interest the report by Wong et al. (1) describing the successful conservative management of a patient suffering from 5 years of primary infertility and persistent atypical polypoid adenomyoma (APA). The management proposed by the authors included a close surveillance of the APA by means of regular hysteroscopic examinations and uterine curettages (every 4–6 months) as well as the administration of the traditional Chinese herbal medication Danggui (Angelica sinensis), which acts as an ovulation inducer. Given the unfavorable outcome of the first pregnancy, lowdose aspirin was also administered to the patient as soon as she achieved her second pregnancy. Recently, we have reported an innovative hysteroscopic technique for the treatment of APA in a 35-year-old infertile woman desiring pregnancy (2). This technique includes four steps, each one being characterized by a pathological analysis: [1] the removal of the APA, [2] the removal of 1283