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Aji_438 364.370Controlled Ovarian Hyperstimulation Changes the Prevalence ofSerum Autoantibodies in In Vitro Fertilization Patients Kadri Haller1,2, Aili Sarapik1, Ija Talja1, Andres Salumets2,3,4, Raivo Uibo1 1Department of Immunology, Institute of General and Molecular Pathology, Centre of Molecular and Clinical Medicine, University of Tartu, Tartu,Estonia;2Department of Obstetrics and Gynecology, University of Tartu, Tartu, Estonia;3Nova Vita Clinic, Centre for Infertility Treatment and Medical Genetics, Haabneeme, Viimsi County, Harjumaa, Estonia;4Institute of Molecular and Cell Biology, University of Tartu, Estonian Biocentre, Tartu, Estonia Autoimmune mechanisms are involved in etiology of female infertility, the medical problem frequently treated by in vitro fertilization (IVF).
Controlled ovarian hyperstimulation (COH) with supraphysiological lev- CorrespondenceRaivo Uibo, Department of Immunology, els of sex hormones is achieved by IVF.
Institute of General and Molecular Pathology, Centre of Molecular and Clinical Medicine,University of Tartu, Ravila Str. 19, Anti-human-ovary and eight common autoantibodies [nuclear (ANA-H, ANA-R on human HEp-2 cell line and rodent antigen, respectively), smooth muscle (SMA), parietal cell, thyroid microsomal, mitochondrial,b2-glycoprotein-I, cardiolipin antibodies] found in IVF patients (n ¼ 129) were analyzed with regard to the number of previous IVF proce- dures and the age of the patient. The changes in autoimmune reactions Haller K, Sarapik A, Talja I, Salumets A, Uibo R. Controlled ovarian hyperstimulationchanges the prevalence of serum Endometriosis and polycystic ovary syndrome were associated with a autoantibodies in in vitro fertilization patients.
higher number of common serum autoantibodies compared with the tu- bal factor infertility (Proportion test, P < 0.05). ANA-R was associatedwith unexplained infertility [adjusted odds ratio (aOR) 8.79, P ¼ 0.038].
SMA correlated with endometriosis (aOR 37.29, P ¼ 0.008), male factorinfertility (aOR 20.45, P ¼ 0.018) and with the previous IVF procedures(aOR 2.87, P ¼ 0.013). There was an overall decrease in the number ofdetectible autoantibodies after COH (Proportion test, P < 0.05).
ConclusionCOH may have a suppressive effect on the humoral immunity by thetime of embryo transfer but more conclusive studies are needed.
ogenesis of infertility is not uniformly understood.
Some of the autoantibodies have been associated A high prevalence of autoimmune mechanisms with certain diseases as patients with endometriosis responsible for reproductive failure has been demon- often possess anti-nuclear (ANA) and anti-smooth strated by others1 and conformed by us.2,3 However, muscle autoantibodies (SMA). Ovarian autoantibod- the impact of a particular autoantibody on the path- ies have been associated with premature ovarian American Journal of Reproductive Immunology 56 (2006) 364–370 ª 2006 The Authors Journal compilation ª 2006 Blackwell Munksgaard COH CHANGES THE PREVALENCE OF SERUM AUTOANTIBODIES IN IVF PATIENTS failure, antiphospholipid and thyroid autoantibodies have been associated with recurrent pregnancyloss.1,4,5 Some studies suggest lesser importance of specific autoantibodies and stress the key role ofoverall activation of the immune system in reduced The Ethics Committee of the University of Tartu approved the study and informed consent was Steroid sex hormones have substantial impact on obtained from all participants after the nature of the both development and modulation of the immune study was explained to them. A total of consecutive system and general susceptibility to autoimmunity.
129 infertile patients (mean age 33.0 years, SD ¼ Steroid hormones exert dose and time dependent 5.5) undergoing IVF-ET at Nova Vita Clinic between actions both locally in the tissues in which they are July 2004 and October 2005 were enrolled in the produced and centrally after entering into the circu- study. The indications for IVF within the study lation.7 These hormones modulate immune system group were as follows: 43.4% (n ¼ 56) tubal factor after extended administration but also during the infertility, 22.5% (n ¼ 29) male factor infertility, menstrual cycle.8,9 Additionally, sex hormones are 16.3% (n ¼ 21) polycystic ovary syndrome (PCOS), implicated in the immune response with dual effects: 9.3% (n ¼ 12) endometriosis and 8.5% (n ¼ 11) estrogens as enhancers of the humoral immunity and unexplained infertility. Patients with other causes of androgens and progesterone as immunosupressors.7,8 infertility as endometrial hyperplasia, myoma uteri, At physiological level, estradiol and especially its ovulatory dysfunction, autoimmune diseases (Hashi- metabolite 16a-hydroxyestrone, may favor autoim- moto’s thyroiditis) or chronic infections were exclu- munity by increasing B cell differentiation and anti- body production as well as by activating T cells.7 The participated, 85 women (65.9%) were about to start effect of progesterone on immunoglobulin (Ig) secre- their first IVF procedure, 26 (20.2%) had had one, tion is believed to be mediated by hormonal effects 10 (7.7%) had had two, and eight (6.2%) had had on immunocompetent cells.9 Testosterone shifts sup- three or more previous IVF procedures. All patients pressor/cytotoxic CD4)CD8+ cells to predominate had been suffering from infertility for at least 1 year over the helper CD4+CD8) lymphocytes among before entering the study. The pregnancy rate (posit- mature thymocytes.8 The altered estradiol/testoster- ive chorionic gonadotropin test) and clinical preg- one ratio and peripheral conversion of sex hormones nancy rate per embryo transfer were 40.5% (51/ are believed to be pathogenic factors for impaired im- 126) and 30.2% (38/126), respectively.
munosupression in several autoimmune diseases.7 Endometriosis and PCOS were diagnosed as repor- In vitro fertilization-embryo transfer (IVF-ET) has ted previously.3 Tubal factor infertility due to the fal- become a promising treatment for infertility of many lopian tube occlusion was diagnosed either by causes. During IVF-ET procedure, multiple follicles hysterosalpingography or diagnostic laparoscopy.11 are enabled to grow and mature by stimulating the The main cause for tubal occlusion was an episode ovaries with the administration of exogenous fol- of infection (pelvic inflammatory disease). Male fac- licle-stimulating hormone (FSH). This procedure is tor infertility was diagnosed when the woman routinely known as controlled ovarian hyperstimula- lacked known reasons for infertility, while her part- tion (COH). COH is associated with rapid increase of ner experienced decreased semen quality.12 Unex- the production of gonadal sex hormones, with the plained infertility was assumed if the woman lacked level of estradiol exceeding at least five to 10 times any of the abovementioned reasons for infertility the estradiol level at the luteal stage of spontaneous and her partner had normal semen quality, but the menstrual cycle.10 In this context, the COH deter- couple had suffered from infertility for more than a mines the hormonal and immunological status at which the embryo transfer takes place.
The blood samples were drawn twice from each The prospective of the present study was to (i) des- patient: (1) during the 3–5 days of the patient’s cribe the autoimmune reactions in IVF patients with spontaneous menstrual cycle before administering different causes of infertility and to analyze the results gonadotropin-relasing hormone (GnRH) agonists/ with regard to the number of previous IVF procedures antagonists and starting the COH; and (2) on the and the age of the patient, and (ii) detect the changes day of oocyte retrieval immediately after the COH.
in autoimmune reactions caused by COH.
The ovarian hormonal stimulation was conducted American Journal of Reproductive Immunology 56 (2006) 364–370 ª 2006 The Authors Journal compilation ª 2006 Blackwell Munksgaard according to either the conventional long protocol 161.1 ± 117.0 pmol/L, progesterone 1.6 ± 1.4 nmol/ using GnRH agonists [n ¼ 7 (5.4%)], or antagonists L, and testosterone 1.5 ± 0.7 nmol/L. The levels of the hormones increased significantly (paired t-test, recombinant FSH. The levels of serum estradiol, P < 0.0001) by the day of the oocyte pick-up (OPU): progesterone, and testosterone were measured using chemiluminescence immunoassay (Immulite 2000Ò 32.3 ± 19.1 nmol/L, and testosterone 3.3 ± 1.9 nmol/ station, Diagnostic Products Corporation, Los Ange- L. The levels of estradiol, progesterone and testoster- one at SPC were similar in all patient groups (data notshown). The level of estradiol at OPU was significantlyhigher in PCOS patients compared with the tubal factor infertility group [medians 6533 (from 885 Stored sera were assayed for the presence of anti- to 45520) pmol/L and 2818 (from 712 to 31130) human ovary (AOA) and common autoantibodies: pmol/L, respectively] (Wilcoxon test, P ¼ 0.017).
nuclear (ANA-H, ANA-R on human HEp-2 cell line Patients with endometriosis, male factor infertility and rodent antigen, respectively), SMA, parietal cell and unexplained infertility demonstrated similar (PCA), thyroid microsomal (TMA) and mitochondrial OPU-estradiol levels as the tubal factor infertility (AMA) antibodies using the indirect immunofloures- group (data not shown). The levels of progesterone cence method as described previously.2 The antibody and testosterone at OPU were similar in all patient levels were expressed as negative or as positive at lower (1:10) or higher (1:100) titers.
Indirect in-house ELISA was used to detect anti- The Prevalence of Autoantibodies in Different Patient Groups at Early Follicular Phase of cardiolipin13 (ACA). The results were expressed in values for weak and strong positive result were 10 All patients who represented autoantibodies followed and 30 EIU for B2-GPI, and 30 and 60 EIU for the GnRH antagonist protocol (94.6%), while the ACA. All immunological tests are clinically avail- patients in the GnRH agonist protocol group (5.4%) able and have been periodically subjected to exter- were negative for all measured autoantibodies. We nal quality assessment by UK NEQAS (Sheffield, did not detect any patients positive for AOA or AMA antibodies. In the group of endometriosis and PCOS,there were more patients positive for at least oneautoantibody at the lower titer (endometriosis only) and at the higher titer than in the group of the tubal To evaluate the statistical difference between auto- antibody levels before and after COH the R 2.3.1 A To evaluate the putative associations between the Language and Environment (Free Software Founda- certain autoantibodies at SPC and the cause of infer- tion, Boston, MA, USA) was used for proportion test tility the logistic regression analysis was used. The with continuity correction, Wilcoxon test, paired logistic regression models for each antibody studied t-test and logistic regression analysis. Patients with were adjusted by the age and the number of previ- tubal factor infertility participated in the study as a ous IVF procedures. The number of previous IVF reference group. A P-value of < 0.05 was considered cycles was only associated with the higher frequency of 1:10 SMA (adjusted OR 2.87, P ¼ 0.013). Higherprevalence of 1:10 SMA was also associated withendometriosis and male factor infertility (adjusted OR 37.29, P ¼ 0.008 and 20.45, P ¼ 0.018) andshowed a tendency to be more frequent in PCOS The Patients’ Hormonal Profile Before and After (adjusted OR 11.19, P ¼ 0.067). Additionally, our model revealed higher frequency of ANA-R 1:10 The following steroid hormone profiles of patients antibodies in unexplained infertility group (adjusted were recorded during the follicular phase of the spon- OR 8.79, P ¼ 0.038) compared with the tubal factor taneous menstrual cycle (SPC): estradiol (mean ± SD) American Journal of Reproductive Immunology 56 (2006) 364–370 ª 2006 The Authors Journal compilation ª 2006 Blackwell Munksgaard COH CHANGES THE PREVALENCE OF SERUM AUTOANTIBODIES IN IVF PATIENTS Table I The prevalence of autoantibodies (Ab) in serum obtained during the 3–5 days of the patients’ spontaneous menstrual cycles *Antibody-positivity at the lower titer was assessed by counting the number of positive tests at the following titers: 1:10 for ANA-R, ANA-H,SMA, TMA and PCA or ACA and B2GP I present at least at the weak positive value.
**Antibody-positivity at the higher titer was assessed by counting the number of positive tests at the following titers: 1:100 for ANA-R, SMA,TMA, 1:10 for PCA and 1:40 for ANA-H or highly positive results for ACA and B2GP I autoantibodies.
N.S., statistically not significant (P > 0.05).
or higher titer, representing the phenomenon of The Dynamics of Autoantibody Levels During the antibody-increase after the COH; (ii) patients with unchanged number of detectible autoantibodies after The increased ANA-R, ANA-H, SMA, TMA and PCA the COH either at lower or at higher titer; or (iii) antibody levels after the COH were measured as chan- patients with fewer autoantibodies detected at OPU ges in titers from negative to positive at the lower tit- than at SPC either at lower or at higher titer, repre- er, or from positive at the lower titer to positive at the senting the phenomenon of antibody-decrease after higher titer. The decrease in antibody levels was the COH. The number of patients with increased assessed by the opposite changes in titers. The increase antibody titer was compared with the number of of ACA and B2GP I levels were assessed in two ways: patients with decreased antibody titer using the pro- (i) by changes from negative to weak positive reading, portion test. Our results showed an overall reduction and from weak positive to highly positive reading in autoantibodies during the COH, as there were sig- (comparisons were done using proportion test); and nificantly more patients who showed a decrease in (ii) as a continuous values (comparisons were done detectible autoantibodies after the COH compared using paired t-test). The decrease of ACA and B2GP I with the patients with increased number of autoanti- levels were detected opposite way to the increase. The bodies (Table II). Same results were obtained for levels of SMA, PCA, TMA, ACA and B2-GP I antibod- patients following only the GnRH antagonist proto- ies did not change during the COH. However, the ANA-H level decreased significantly (proportion testbetween the patients with decreased and increasedantibody levels, P < 0.05). In comparison, the level of Table II The comparison of the frequency of patients showing B2-GP I antibody raised during the COH (mean the increase or the decrease in number of detected levels ± SD before and after COH were 2.0 ± 8.4 and 2.3 ± 6.9 EIU, P ¼ 0.031, paired t-test), but this change was insufficient to increase the number of tests above the cut-off (proportion test, P > 0.05). The same changes in ANA-H and B2-GP I antibody levels were detected for patients studied with only the GnRH antagonist protocol (data not shown).
The number of patients was counted for both situations follow-ing the COH: amore autoantibodies were detected at OPU than The Changes in Autoantibodies During the COH at SPC either at lower or higher titer, or bfewer autoantibodieswere detected at OPU than at SPC either at lower or higher After the COH, we counted patients falling into the following groups: (i) patients with more autoanti- *Statistically significant difference (proportion test, P < 0.05) bodies detected at OPU than at SPC either at lower American Journal of Reproductive Immunology 56 (2006) 364–370 ª 2006 The Authors Journal compilation ª 2006 Blackwell Munksgaard the level of ANA-H decreased, while only the level of B2-GPI increased slightly. Regardless of the high A large variety of non-organ- and organ-specific prevalence of autoantibodies in the group of IVF autoantibodies are associated with female infertil- patients1 and the hazardous effect of anti-ovarian,14 ity.1,14 Therefore, it has been challenging to look for a ANA and antiphospholipid1,16 antibodies on embryo particular antibody most strongly associated with cer- as well as on early pregnancy, only a few studies tain cause of infertility.1,4,5 Concordant with previous have been conducted so far to explore the effect of studies, we found that a low titer of ANA (detected COH on the levels of common autoantibodies. Fisch by rodent antigen substrate) was strongly associated et al.21 showed no significant changes in the levels with the unexplained infertility. The association was of ANA or ACA during the hormonal stimulation.
independent of the age of the patient and the number Similarly, Monnier-Barbarino et al.22 concluded the of previous IVF procedures. Because ANA has been absence of influence of ovarian stimulation (per- associated with early implantation failure,1 these formed by classical long GnRH agonist protocol) on antibodies may promote infertility in otherwise clinic- anti-ovarian autoimmunity. We were not able to ally healthy woman. We also showed an association compare two protocols used in ovarian stimulation – between the presence of lower titer SMA and endo- GnRH antagonists and agonists, because of only metriosis and male factor infertility. In addition, SMA seven (5.4%) patients followed the agonist protocol was the only antibody in our study which correlated none of whom represented the autoantibodies stud- positively with the previous use of IVF procedures in ied. Thus, our results are restricted to GnRH antag- an age-independent fashion. The association between the production of SMA and infertility due to the male The activating effect of estrogens on the humoral factor could not be easily explained. In the group of immune system has been reported by studying patients with male factor infertility, unexplained or women during menstrual cycles, by evaluating the undetected subfertility of the woman cannot always patients suffering from rheumatoid arthritis or sys- be ruled out. In addition, there is clear evidence that temic lupus erythematosus, and by using animal the production of SMA can be caused by persistent models.7–9 The level of serum estradiol is typically viral infection and these antibodies alter the fallopian within the physiological range in abovementioned tube function.1 Although we were not aware of any autoimmune diseases7 and serum levels used in ani- viral infections among our IVF patients one cannot mal studies were five to 14 times lower than the lev- exclude some similarities between the immune sys- els found during pregnancy.23–25 However, it has tem dysregulation in chronic inflammation and endo- been demonstrated for chronic inflammatory dis- metriosis or repeated IVF procedures. An increase of eases that depending on the concentration, estradiol autoantibodies after repeated IVF attempts has previ- can exert the opposite effect on immune system.7 In our study, the production of estradiol increased rap- Rather than the presence of one particular autoan- idly during COH and the levels reached the values of tibody, the detection of activation of immune sys- 10 times higher than those at luteal stage of sponta- tem, in general, can help to predict the patient’s neous menstrual cycle. In addition to the supraphys- fecundity and the outcome of IVF-ET treatment.6,17 We analyzed the association between the cause of immunosuppressive testosterone and progesterone7,8 infertility and the autoimmune reaction, with regard also increased. Therefore, the specific changes in the to the number of autoantibodies detected. Our levels of all three sex hormone associated with COH results showed that infertile patients with endomet- may explain the decrease in number of autoantibod- riosis and PCOS were associated with significantly higher number of common serum autoantibodies Although the effect of sex hormones on immune compared with the women with tubal factor infertil- reactions can take place within a short period of ity. The higher prevalence of autoantibodies in these time9,24 the produced autoantibodies could stay patient groups compared with the fertile controls has in the circulation for a longer period. The time been demonstrated by many authors.2,18–20 period for COH in our study was 9–12 days. IgG has It was somewhat surprising to us, that the number a half-life of 7–23 days, depending on the specific of autoantibodies detected after the COH showed an subclass.26 However, in case of autoimmunity, the overall decrease. Of all the autoantibodies studied, considerable increase in the catabolic rate of IgG American Journal of Reproductive Immunology 56 (2006) 364–370 ª 2006 The Authors Journal compilation ª 2006 Blackwell Munksgaard COH CHANGES THE PREVALENCE OF SERUM AUTOANTIBODIES IN IVF PATIENTS 3 Haller K, Mathieu C, Rull K, Matt K, Be´ne´ MC, expected half-life to less than a third of the normal Uibo R: IgG, IgA and IgM antibodies against FSH: value.27–29 Our data along with the data from litera- serological markers of pathogenic autoimmunity or of ture suggest that COH may have an effect on the normal immunoregulation? Am J Reprod Immunol humoral immunity by the time of embryo transfer but profound studies are still required to further 4 Van Voorhis BJ, Stovall DW: Autoantibodies and explore this effect. A question of how these changes infertility: a review of the literature. J Reprod Immunol in autoimmune reactions caused by COH could be related to the outcome of IVF treatment is the prior- 5 Mecacci F, Parretti E, Cioni R, Lucchetti R, Magrini A, La Torre P, Mignosa M, Acanfora L, Mello G: Thyroid autoimmunity and its association with non-organ-specific antibodies and subclinical alterations of thyroid function in women with a history ofpregnancy loss or preeclampsia. J Reprod Immunol Our results indicate that different forms of infertility are associated with various autoimmune distur- 6 Gleicher N: Antiphospholipid antibodies (aPL) affect bances along with the slight deviations in the profile in vitro fertilization (IVF) outcome. Am J Reprod of autoantibodies. We showed that the ovarian hor- monal stimulation and repeatedly performed IVF 7 Cutolo M, Sulli A, Capellino S, Villaggio B, procedures themselves could conversely modulate Montagna P, Seriolo B, Straub RH: Sex hormones the autoimmune reactions. These data suggest that influence on the immune system: basic and clinical COH may have a suppressive effect on the humoral aspects in autoimmunity. Lupus 2004; 13:635–638.
immunity by the time of embryo transfer but further 8 Tanriverdi F, Silveira LFG, MacColl GS, Bouloux PMG: The hypothalamic-pituitary-gonadal axis:immune function and autoimmunity. J Endocrinol2003; 176:293–304.
9 Beagley KW, Gockel CM: Regulation of innate and This study was supported by the Estonian Science adaptive immunity by the female sex hormones Foundation (Grants no. 6498 and 6514) and the oestradiol and progesterone. FEMS. Immunol Med Estonian Ministry of Education and Science (Core grants no. 0182582Cs03 and 0182586s03). We thank 10 Orvieto R, Schwartz A, Bar-Hava I, Abir R, Ashkenazi Anu Kaldmaa, Ku¨llike Koppel and Ele Prans from J, La-Marca A, Ben-Rafael Z: Controlled ovarian the Department of Immunology of the University of hyperstimulation - a state of endothelial activation.
Am J Reprod Immunol 2000; 44:257–260.
Tartu, Estonia for their skillful laboratory assistance.
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14 Monnier-Barbarino P, Forges T, Be´ne´ MC: Gonadal antibodies interfering with female reproduction. Best 1 Geva E, Amit A, Lerner-Geva L, Lessing JB: Pract Res Clin Endocrinol Metab 2005; 19:135–148.
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El Juez y la Conectividad – el nuevo principio de la José Eduardo de Resende Chaves Júnior1 Aunque haya virado cliché enaltecer el potencial colectivo de la red, en el Poder Judicial eso todavía es un gran tabú, pues la decisión judicial, mismo cuando proferida de forma colegiada, es fruto todavía de un proceso de convicción profundamente monocrático. Sin perquirir sobre las compleja