Obstetrics & Gynecology:
Serum and Follicular Fluid Cytokines in Polycystic Ovary Syndrome During Stimulated Cycles
Amato, Giovanni MD; Conte, Marisa MD; Mazziotti, Gherardo MD; Lalli, Eleonora MD; Vitolo, Gabriella MD; Tucker, Arthur T. PhD; Bellastella, Antonio MD; Carella, Carlo MD; Izzo, Alfredo MD
Institutes of Endocrinology and Obstetrics & Gynecology, 2nd University of Naples, Naples, Italy; and The Ernest Cooke Microvascular Unit, St. Bartholomew's Hospital, London, United Kingdom.
Address reprint requests to: Giovanni Amato, MD, Via Orsi 33, 80128 Napoli, Italy.; E-mail: firstname.lastname@example.org.
Received July 15, 2002. Received in revised form November 30, 2002. Accepted December 4, 2002.
OBJECTIVE: To investigate the serum and intrafollicular tumor necrosis factor–α and interleukin-6 concentrations in infertile women with polycystic ovary syndrome (PCOS) undergoing in vitro fertilization (IVF).
METHODS: Thirty-one patients with PCOS undergoing IVF were studied. Thirty-nine normally ovulating women matched for age and body mass index and undergoing IVF for male infertility were the control group. Serum tumor necrosis factor–α, interleukin-6, and estradiol levels were assayed before recombinant follicle-stimulating hormone stimulation under gonadotropin-releasing hormone analogue suppression and 34–36 hours after human chorionic gonadotropin (hCG) administration at the time of the oocyte retrieval. Cytokine and estradiol concentrations were also evaluated in the follicular fluids obtained at the time of oocyte retrieval.
RESULTS: The patients with PCOS had higher serum and follicular fluid tumor necrosis factor–α and interleukin-6 concentrations (P < .001) and lower follicular fluid estradiol levels (P < .05) than control women. In both groups, the serum tumor necrosis factor–α, interleukin-6, and estradiol values increased significantly after hCG stimulation. In both groups, the follicular fluid cytokine concentrations were higher than those found in the serum. In the PCOS women the follicular fluid tumor necrosis factor–α values were significantly and inversely correlated to the follicular fluid estradiol values (ρ = −0.79; P < .001); this correlation was not found in the control subjects.
CONCLUSION: In infertile women with PCOS, 1) serum and follicular fluid interleukin-6 and tumor necrosis factor–α values were higher than those found in control women, 2) the cytokine concentrations were higher in the follicular fluid than in the serum, and 3) the intrafollicular tumor necrosis factor–α concentrations were significantly and inversely correlated to the estradiol levels. These results suggest an involvement of the immune system in PCOS.
Polycystic ovary syndrome (PCOS) is the most frequently occurring ovarian disorder associated with impaired ovulation. 1 Immune mechanisms may play an important role in determining PCOS, as suggested by the high concentrations of white blood cells in polycystic ovaries, 2 the high prevalence of antiovarian antibodies, 3 and the altered lymphocyte subset in peripheral blood of women with the disease. 4
Cytokines, soluble polypeptides of immunological origin, are local regulators of ovarian function. 5 They are involved in regulation of gonadal steroid secretion and corpus luteum function as well as in the modulation of the ovulatory process. 6–8 Tumor necrosis factor–α and interleukin-6 have been shown to exert a pleiotropic effect on ovary function. 7,9–14 Both cytokines have been shown to be in the follicular fluid, 15–17 suggesting their production by the granulosa cells. 10,18 Indeed, the gonadotropins can modulate cytokine production, 10 causing marked fluctuations in relation to the different stages of folliculogenesis. 19 Recently, the role of these cytokines in PCOS has suggested that they are involved in ovary hyperstimulation 20 as well as in hyperandrogenism of PCOS. 21 However, the data reported are few, and the results are controversial. 17,20–23
In this controlled study, our purpose was to evaluate the serum and follicular fluid levels of tumor necrosis factor–α and interleukin-6 in infertile women with PCOS undergoing in vitro fertilization (IVF). The evaluation of women during a standardized ovarian stimulation protocol allowed us to obtain follicular fluids from follicles of the same developmental phase and serum specimens at specific time points. By this model, we investigated the cytokine behavior in a temporal relationship with the gonadotropin-mediated stimulation and different stages of folliculogenesis.
MATERIALS AND METHODS
Our study group consisted of 31 infertile patients with PCOS who underwent IVF treatment. Polycystic ovary syndrome was diagnosed based upon the elevation of one or more plasma androgen levels (free testosterone greater than 0.8 ng/mL, total testosterone greater than 70 ng/dL, dehydroepiandrosterone sulfate greater than 300 ng/dL), chronic oligo- (six or fewer menses per year) or amenorrhea, and the presence of ten or more follicles (2–10 mm in diameter) in one or both ovaries with an enlarged stroma at ultrasound evaluation. 24,25 21-hydroxylase deficiency, hyperprolactinemia, and androgen-secreting tumors were excluded in these patients by appropriate diagnostic tests. The indications of IVF in PCOS were failure of five to six cycles of increasing doses of clomiphene citrate and failure to conceive after ovulation induced by gonadotropins. Thirty-nine normally ovulating women diagnosed with male factor infertility of greater than 3 years and undergoing IVF, with age and body mass index (BMI) comparable to the study groups, were selected as the control group (Table 1). Regular menses and levels of progesterone above 10 ng/mL in the luteal phase of the preceding menstrual cycles demonstrated normal ovulation. At study entry, the exclusion criteria were 1) BMI above 30 kg/m2, to avoid the effects of obesity on serum tumor necrosis factor–α levels 26,27; 2) diabetes or any other systemic disease; 3) thyroid diseases; and 4) treatment with insulin-sensitizing agents in the last year.
The study was approved by the local ethical committee. All patients gave written informed consent before participation in the study, according to the Declaration of Helsinki of 1975, revised 1983.
As previously described, 28 oocyte retrieval was performed 34–36 hours after human chorionic gonadotropin (hCG) administration with the use of transvaginal, sonographically guided puncture. Samples of follicular fluids were obtained from 176 follicles (range 18–24 mm) at oocyte collection after recombinant follicle-stimulating hormone (rFSH) and hCG administration in all patients participating in IVF. For each patient, at least two follicles were aspirated to provide a more accurate evaluation of the intrafollicular cytokine concentrations. Each follicle was aspirated separately, and fluids were collected in a 15-mL conical tube. Subsequently, for each individual, a pooled follicular fluid sample was obtained by combining equal aliquots from two or more fluid collection devices. Part of each sample was centrifuged (2000g) to separate serum.
Tumor necrosis factor–α, interleukin-6, and estradiol (E2) levels were assayed in the follicular fluids obtained at oocyte collection; they were also evaluated in sera obtained from all IVF patients before rFSH stimulation under gonadotropin-releasing hormone analogue suppression (suppression phase) and 34–36 hours after hCG administration at the time of the oocyte retrieval (pickup phase).
Follicular fluid and sera were processed rapidly, and all samples were stored at −20C. The assays were performed at the end of the enrollment of all 70 women.
Interleukin-6 and tumor necrosis factor–α were measured in serum and follicular fluid by a solid-phase enzyme-linked immunosorbent assay (Medgenix Diagnostics, Fleurus, Belgium). Intrassay coefficients of variation in our laboratory were 4.2% for interleukin-6 and 3.3% for tumor necrosis factor–α, respectively. Estradiol was measured in serum and follicular fluid by a radioimmunoassay commercial kit (Sorin, Saluggia, Italy). Intra-and interassay coefficients obtained were between 5.1% and 11.3% for E2.
The Kolmogorov–Smirnov test was applied to both groups. The results were significant, suggesting an asymmetric distribution of the data for each variable. Median and range were used to present the data, unless otherwise indicated. Paired and unpaired data were compared using Wilcoxon signed-rank and Mann–Whitney tests. The Spearman rank correlation was used to demonstrate correlation between variables. Hypothesis tests were two sided, with probability values of less than 5% taken to represent statistical significance.
Table 2 shows the results of tests performed on sera from the two groups of women. In the suppression phase, PCOS patients showed serum tumor necrosis factor–α and interleukin-6 values significantly higher than those found in the control group; however, E2 values did not statistically differ between the two groups (P = .053). No correlation was found between serum tumor necrosis factor–α and E2 (PCOS group: ρ = −0.26, P = .15; control group: ρ = 0.05, P = .74) or between serum interleukin-6 and E2 (PCOS group: ρ = −0.25, P = .17; control group: ρ = 0.17, P = .29). After gonadotropin stimulation (pickup phase), the serum values of all three parameters increased significantly both in women with PCOS and in control subjects. At the pickup phase, the patients with PCOS showed serum tumor necrosis factor–α and interleukin-6 values significantly higher than those of the control group, whereas the difference in E2 values was not significant (Table 2). The median percentage of variation of tumor necrosis factor–α and interleukin-6 in the two groups did not significantly differ (data not shown).
Table 3 shows the result of tests performed on follicular fluids from the two groups of women. Polycystic ovary syndrome women showed higher follicular fluid tumor necrosis factor–α and interleukin-6 levels and lower follicular fluid E2 levels than those found in the control group. In both groups, the follicular fluid interleukin-6 and tumor necrosis factor–α levels were higher than those found in the serum (P < .001 for both comparisons). In patients with PCOS, follicular fluid tumor necrosis factor–α levels were significantly correlated to follicular fluid interleukin-6 (ρ = 0.36, P < .05) and follicular fluid E2 levels (ρ = −0.79, P = .001) (Figure 1). No significant correlation was found between follicular fluid interleukin-6 and follicular fluid E2 values in patients with PCOS (ρ = −0.23, P = .21). In the control group, no significant correlation was found between follicular fluid interleukin-6 and tumor necrosis factor–α (ρ = 0.08, P = .61), follicular fluid interleukin-6 and E2 (ρ = −0.06, P = .69), and follicular fluid tumor necrosis factor–α and E2 values (ρ = 0.21, P = .18).
In this study, we observed that infertile women with PCOS undergoing IVF showed higher serum and follicular fluid tumor necrosis factor–α and interleukin-6 levels than the control subjects. Moreover, we demonstrated that follicular fluid concentrations of tumor necrosis factor–α were significantly and inversely correlated to follicular fluid E2 levels.
The role of the cytokines in PCOS has been investigated, with controversial results in relation to the different analysis procedures and the different study populations. 17,20–23 We choose to evaluate the tumor necrosis factor–α and interleukin-6 values in infertile PCOS women undergoing IVF. This study model was suggested by the need to recognize the different phases of the folliculogenesis that have been shown to markedly influence cytokine production. Previous studies reported high serum tumor necrosis factor–α concentrations in nonstimulated PCOS women. 21,22 In the present study we confirmed this finding, and we found a strict correlation between tumor necrosis factor–α and interleukin-6 values. These findings disagree with previous observations that do not demonstrate any significant increase of the latter cytokine in PCOS patients in the course of spontaneous cycles. 17,20 Furthermore, we demonstrated that such difference was evident both in the early phase of the folliculogenesis and at the time of ovulation. The gonadotropin stimulation, however, induced a significant and comparable increase of interleukin-6 and tumor necrosis factor–α either in the patients with PCOS or in the normal group. This finding is suggestive for a physiologic modulation of cytokine secretion by these pituitary hormones, although in our study protocol the gonadotropin stimulation was performed with pharmacological doses. Indeed, previous studies demonstrated that FSH was able to induce interleukin-6 expression from granulosa cells, 10 and a possible regulation of interleukin-6 expression by luteinizing hormone (LH) was also suggested. 29 The rise of interleukin-6 levels could be in relation to the angiogenesis occurring during the ovarian follicular development. 12
In our PCOS patients, the intrafollicular interleukin-6 and tumor necrosis factor–α concentrations were higher than those found in the serum, suggesting a local production for these cytokines. Indeed, even if both cytokines are mainly produced by white blood cells, they can be also elaborated by granulosa cells. 30 Besides the source of production, however, the high intrafollicular levels of tumor necrosis factor–α and interleukin-6, as well as the inverse correlation between the tumor necrosis factor–α and E2 values, could be suggestive of an involvement of these cytokines in the pathophysiology of PCOS. This conclusion follows the hypothesis of the existence of a relationship between the endocrine and immune systems in such disease, 4 as demonstrated in other pathologic diseases of the reproductive system. 31,32 Because the present study was performed in a homogeneous group of PCOS patients undergoing stimulation, we cannot demonstrate either the pathophysiologic mechanisms or the eventual involvement of the above cytokines in all pathologic aspects of the syndrome. Actually, both interleukin-6 and tumor necrosis factor–α seem to exert many effects at the reproductive axis. In particular, interleukin-6 has a stimulatory effect on LH secretion, 29,33 which pulse secretion is impaired in the patients with PCOS. 34 Also, tumor necrosis factor–α has been shown to influence folliculogenesis, follicular maturation, 7,9,10 and gonadotropin-induced steroidogenesis by stimulating the proliferation of theca-luteinized and interstitial cells, 35 androgen synthesis, 36 and inhibition of differentiation of cultured granulosa cells. 37 Moreover, high tumor necrosis factor–α concentrations in follicular fluid were linked to a poor quality of oocytes, 31,32,38 and some evidence suggests that tumor necrosis factor–α could mediate insulin resistance, 39 which is a common finding in patients with PCOS. In addition to these effects, the immunological properties of tumor necrosis factor–α should be considered in this physiopathologic context. Tumor necrosis factor–α is a proinflammatory cytokine associated with the Th1 immune response. 40 As a Th1-inducing factor, tumor necrosis factor–α seems to play a critical role in modulating the apoptotic process in experimental models of autoimmune diseases. 41 Abnormality in apoptotic process has been described in PCOS, 42 and the modulatory role of type 1 cytokines has been investigated. 43 The results of our study suggest an involvement of the immune system in the pathogenesis of disease. 3 The future characterization of these physiopathologic aspects might favor new diagnostic and therapeutic perspectives in the management of patients with PCOS.
Our study demonstrated that in infertile women with PCOS in the course of IVF, 1) serum interleukin-6 and tumor necrosis factor–α levels were higher than those found in control women, 2) the cytokine concentrations were higher in the follicular fluid than in the serum, and 3) the intrafollicular tumor necrosis factor–α concentrations were significantly and inversely correlated to the E2 levels. Further studies are needed to clarify both the specific role of these cytokines in the disease and the eventual application of cytokine measurement, as well as the anticytokine treatment, in the management of patients with PCOS.
1. Franks S, White DM. Prevalence of and etiological factors in polycystic ovarian syndrome. Ann N Y Acad Sci 1993; 687:112–4.
2. Bukulmez O, Arici A. Leukocytes in ovarian function. Hum Reprod Update 2000;6:1–15.
3. Fenichel P, Gobert B, Carré Y, Barbarino-Monnier P, Hiéronimus S. Polycystic ovary syndrome in autoimmune disease. Lancet 1999;353:2210.
4. Turi A, Di Prospero F, Mazzarini A, Costa M, Cignitti M, Garzetti GG, et al. Lymphocytes subset in hyperandrogenic women with polycystic ovarian disease. Acta Eur Fertil 1988;19:155–7.
5. Adashi EY. The potential relevance of cytokines to ovarian physiology; the emerging role of resident ovarian cells of the white blood cell series. Endocr Rev 1990;11:454–64.
6. Adashi EY. Cytokine-mediated regulation of ovarian function: Encounters of a third kind. Endocrinology 1989;124:2043–5.
7. Adashi EY, Resnick CE, Packman JN, Hurwitz A, Payne DW. Cytokine-mediated regulation of ovarian function: tumor necrosis factor α inhibits gonadotropin-supported progesterone accumulation by differentiating and luteinized murine granulosa cells. Am J Obstet Gynecol 1990; 162:889–99.
8. Garcia-Velasco JA, Arici A. Chemokines and human reproduction. Fertil Steril 1999;71:983–93.
9. Roby KF, Terranova PF. Tumor necrosis factor alpha alters follicular steroidogenesis in vitro. Endocrinology 1988;123:2952–4.
10. Zolti M, Meirom R, Shemesh M, Wollach D, Mashiach S, Shore L, et al. Granulosa cells as source and target organ for tumor necrosis α. FEBS Lett 1990;261:253–5.
11. Kishimoto T. The biology of interleukin-6. Blood 1989; 74:1–10.
12. Motro B, Itin A, Sachs L, Keshet E. Pattern of interleukin 6 gene expression in vivo
suggests a role for this cytokine in angiogenesis. Proc Natl Acad Sci U S A 1990;87:3092–6.
13. Adashi EY, Resnick CE, Croft CS, Payne D. Tumor necrosis factor-α inhibits gonadotropin hormonal action in nontransformed ovarian granulosa cells. J Biol Chem 1989;264:11591–7.
14. Mandrup-Poulsen T, Nerup J, Reimers JI, Pociot F, Andersen HU, Karlsen A, et al. Cytokine and the endocrine system. I. The immunoendocrine network. Eur J Endocrinol 1995;133:660–71.
15. Buyalos RP, Watson JM, Martinez-Maza O. Detection of interleukin-6 in human follicular fluid. Fertil Steril 1992; 57:1230–4.
16. Zolti M, Bider D, Seidman DS, Mashiach S, Ben-Rafael Z. Cytokine levels in follicular fluid of polycystic ovaries in patients treated with dexamethasone. Fertil Steril 1992;57:501–4.
17. Jasper M, Norman RJ. Immunoactive interleukin-1 beta and tumour necrosis factor-alpha in thecal, stromal and cell granulosa cell cultures from normal and polycystic ovaries. Hum Reprod 1995;10:1352–4.
18. Gorospe WC, Hughes FM, Spangelo BL. Interleukin-6: Effects on and production by rat granulosa cells in vitro
. Endocrinology 1992;130:1750–2.
19. Brannstrom M, Friden BE, Jasper M, Norman RJ. Variations in peripheral blood levels of immunoreactive tumor necrosis factor alpha (TNFalpha) throughout the menstrual cycle and secretion of TNFalpha from the human corpus luteum. Eur J Obstet Gynecol Reprod Biol 1999; 83:213–7.
20. Pellicer A, Albert C, Mercader A, Bonilla-Musoles F, Remohì J, Simòn C. The pathogenesis of ovarian hyper-stimulation syndrome: In vivo studies investigating the role of interleukin-1β, interleukin-6, and vascular endothelial growth factor. Fertil Steril 1999;71:482–9.
21. Escobar-Morreale HF, Calvo RM, Sancho J, San Millàn JL. TNF-α and hyperandrogenism: A clinical, biochemical, and molecular genetic study. J Clin Endocrinol Metab 2001;86:3761–7.
22. Gonzalez E, Thusu K, Abdel-Rahman E, Prabhala A, Tomani M, Dandona P. Elevated serum levels of tumor necrosis factor alpha in normal-weight women with polycystic ovary syndrome. Metabolism 1999;48:437–41.
23. Deshpande RR, Chang MY, Chapman JC, Micheal SD. Alteration of cytokine production in follicular cystic ovaries induced in mice by neonatal estradiol injection. Am J Reprod Immunol 2000;44:80–8.
24. Adams J, Franks S, Polson DW, Mason HD, Abdulwahid N, Tucker M. Multifollicular ovaries: Clinical and endocrine features and response to pulsatile gonadotrophin releasing hormone. Lancet 1985;2:1375–8.
25. Dunaif A, Givens JR, Haseltine F, Merriam GR, eds. The polycystic ovary syndrome. Boston: Blackwell Scientific Publications, 1992.
26. Katsuki A, Sumida Y, Murashima S, Murata K, Takarada Y, Ito K, et al. Serum levels of tumor necrosis factor-α are increased in obese patients with noninsulin-dependent diabetes mellitus. J Clin Endocrinol Metab 1998;83:859–62.
27. Dandona P, Weinstock R, Thusu K, Abdel-Rahaman E, Aljada A, Wadden T. Tumor necrosis factor-α in sera of obese patients: Fall with weight loss. J Clin Endocrinol Metab 1998;83:2907–10.
28. Amato G, Izzo A, Tucker A, Bellastella A. Insulin-like growth factor binding protein-3 reduction in follicular fluid in spontaneous and stimulated cycles. Fertil Steril 1998;70:141–4.
29. Loret de Mola JR, Baumgardner GP, Goldfarb JM, Friedlander MA. Ovarian hyperstimulation syndrome: Preovulatory serum concentrations of interleukin-6, interleukin-1 receptor antagonist and tumor necrosis factopr-alpha cannot predict its occurence. Hum Reprod 1996;11:1377–80.
30. Castilla JA, Sampaio A, Molina R, Samaniego F, Mozas J, Vergara F, et al. Mononuclear cell subpopulations in human follicular fluid from stimulated cycles. Am J Reprod Immunol 1990;22:127–9.
31. Cianci A, Calogero AE, Palumbo MA, Burrello N, Ciotta L, Palumbo G, et al. Relationship between tumour necrosis factor α and sex steroid concentrations in the follicular fluid of women with immunological infertility. Hum Reprod 1996;11:265–8.
32. Carlberg M, Nejaty J, Fröysa B, Guan Y, Söder O, Bergqvist A. Elevated expression of tumour necrosis factor α in cultured granulosa cells from women with endometriosis. Hum Reprod 2000;15:1250–5.
33. Cannon JG. Adaptive interactions between cytokines and the hypothalamic-pituitary-gonadal axis. Ann N Y Acad Sci 1998;856:234–42.
34. Kazer RR, Kessel B, Yen SS. Circulating luteinizing hormone pulse frequency in women with polycystic ovary syndrome. J Clin Endocrinol Metab 1987;65:233–6.
35. Spaczynski RZ, Arici A, Duleba AJ. Tumor necrosis factor-α stimulates proliferation of rat ovarian theca-interstitial cells. Biol Reprod 1999;61:993–8.
36. Roby KF, Terranova PF. Effects of tumor necrosis factor α in vitro on steroidogenesis of healthy and atretic follicles of the rat: Theca as a target. Endocrinology 1990;126:2711–8.
37. Darbon JM, Oury F, Laredo J, Bayard F. Tumor necrosis factor-α inhibits follicle-stimulating hormone-induced differentiation in cultured rat granulosa cells. Biochem Biophys Res Commun 1989;163:1038–46.
38. Lee KS, Joo BS, Na YJ, Yoon MS, Choi OH, Kim WW. Relationship between concentrations of tumor necrosis factor-alpha and nitric oxide in follicular fluid and oocyte quality. J Assist Reprod Genet 2000;17:222–8.
39. Paolisso G, Rizzo MR, Mazziotti G, Tagliamonte MR, Gambardella A, Rotondi M, et al. Advancing age and insulin resistance: Role of plasma tumor necrosis alpha. Am J Physiol 1998;275:E294–9.
40. Vassalli P. The pathophysiology of tumor necrosis factors. Annu Rev Immunol 1992;10:411–52.
41. Wang SH, Bretz JD, Phelps E, Mezosi E, Arscott PL, Utsugi S, et al. A unique combination of inflammatory cytokines enhances apoptosis of thyroid follicular cells and transforms nondestructive to destructive thyroiditis in experimental autoimmune thyroiditis. J Immunol 2002; 168:2470–4.
42. Homburg R, Amsterdam A. Polysystic ovary syndrome–loss of the apoptotic mechanism in the ovarian follicles? J Endocrinol Invest 1998;21:552–7.
43. Giudice LC. Growth factor action on ovarian function in polycystic ovary syndrome. Endocrinol Metab Clin North Am 1999;28:325–39.
This article has been cited 38 time(s).
Fertility and SterilityOntogeny of the ovary in polycystic ovary syndromeFertility and Sterility
Gynecologie Obstetrique & FertiliteImpact of polycystic ovary syndrome on oocyte and embryo qualityGynecologie Obstetrique & Fertilite
Human Reproduction UpdateObesity and the role of gut and adipose hormones in female reproductionHuman Reproduction Update
Human ReproductionCytokine and hormonal profile in blood serum and follicular fluids during ovarian stimulation with the multidose antagonist or the long agonist protocolHuman Reproduction
International Journal of AndrologyEffects of tumour necrosis factor alpha and interleukin-6 on progesterone and calcium ionophore-induced acrosome reactionInternational Journal of Andrology
Archives of Medical Science
L-carnitine and assisted reproduction
Archives of Medical Science, 5():
Evaluation of leptin, interleukin-1 beta, tumor necrosis factor-alpha and vascular endothelial growth factor in serum and follicular fluids of women undergoing controlled ovarian hyperstimulation as prognostic markers of ICSI outcome
In Vivo, 18(5):
Journal of Reproductive Medicine
Lipid peroxidation in follicular fluid of women with polycystic ovary syndrome during assisted reproduction cycles
Journal of Reproductive Medicine, 52(8):
Gynecological EndocrinologyPlasma cytokines in obese women with polycystic ovary syndrome, before and after metformin treatmentGynecological Endocrinology
American Journal of Reproductive ImmunologyIgG-antiphospholipid antibodies in follicular fluid of IVF-ET patients are related to low fertilization rate of their oocytesAmerican Journal of Reproductive Immunology
Fertility and SterilityL-Carnitine decreases DNA damage and improves the in vitro blastocyst development rate in mouse embryosFertility and Sterility
Gynecological EndocrinologyComparison of follicular fluid and serum cytokine concentrations in women undergoing assisted reproductive treatment with GnRH agonist long and antagonist protocolsGynecological Endocrinology
Human ReproductionSerum and follicular resistin levels in women with polycystic ovarian syndrome during IVF-stimulated cyclesHuman Reproduction
Journal of Clinical Endocrinology & MetabolismC-reactive protein before and after weight loss in overweight women with and without polycystic ovary syndromeJournal of Clinical Endocrinology & Metabolism
Fertility and SterilityThe role of the endogenous opioid system in polycystic ovary syndromeFertility and Sterility
Best Practice & Research in Clinical Obstetrics & GynaecologyThe pathogenesis of infertility and early pregnancy loss in polycystic ovary syndromeBest Practice & Research in Clinical Obstetrics & Gynaecology
American Journal of Reproductive ImmunologySerum IL-6 Level May Have Role in the Pathophysiology of Unexplained InfertilityAmerican Journal of Reproductive Immunology
Biology of ReproductionImmunity and beta-endorphin concentrations in hypothalamus and plasma in rats with steroid-induced polycystic ovaries: Effect of low-frequency electroacupunctureBiology of Reproduction
Endocrine ReviewsThe molecular-genetic basis of functional hyperandrogenism and the polycystic ovary syndromeEndocrine Reviews
Journal of Clinical Endocrinology & MetabolismHyperglycemia alters tumor necrosis factor-alpha release from mononuclear cells in women with polycystic ovary syndromeJournal of Clinical Endocrinology & Metabolism
Fertility and SterilityThe effect of serum and intrafollicular insulin resistance parameters and homocysteine levels of nonobese, nonhyperandrogenemic polycystic ovary syndrome patients on in vitro fertilization outcomeFertility and Sterility
Human ReproductionFEM1A and FEM1B: novel candidate genes for polycystic ovary syndromeHuman Reproduction
Mediators of InflammationMediators of Inflammation in Polycystic Ovary Syndrome in Relation to AdiposityMediators of Inflammation
Fertility and SterilityThe levels of steroid hormones and cytokines in individual follicles are not associated with the fertilization outcome after intracytoplasmic sperm injectionFertility and Sterility
Molecular EndocrinologyInterleukin-1 alpha-induced chemokines in mouse granulosa cells: Impact on keratinocyte chemoattractant chemokine, a CXC subfamilyMolecular Endocrinology
Human Reproduction UpdateMacrophage contributions to ovarian functionHuman Reproduction Update
Fertility and SterilityIncreased acylation-stimulating protein, C-reactive protein, and lipid levels in young women with polycystic ovary syndromeFertility and Sterility
Hormone ResearchDeterminants of Interleukin-6 and C-Reactive Protein Vary in Polycystic Ovary Syndrome, as Do Effects of Short- and Long-Term Metformin TherapyHormone Research
Journal of Clinical Endocrinology & MetabolismEthinylestradiol-drospirenone, flutamide-metformin, or both for adolescents and women with hyperinsulinemic hyperandrogenism: Opposite effects on adipocytokines and body adiposityJournal of Clinical Endocrinology & Metabolism
Fertility and SterilitySerum levels of soluble vascular cell adhesion molecule-1, tumor necrosis factor-alpha, and interleukin-6 in in vitro fertilization cyclesFertility and Sterility
Journal of Clinical Endocrinology & MetabolismCentral fat excess in polycystic ovary syndrome: Relation to low-grade inflammation and insulin resistanceJournal of Clinical Endocrinology & Metabolism
Metabolism-Clinical and ExperimentalPlasma interleukin 6 levels are elevated in polycystic ovary syndrome independently of obesity or sleep apneaMetabolism-Clinical and Experimental
Human ReproductionOvarian leukocyte distribution and cytokine/chemokine mRNA expression in follicular fluid cells in women with polycystic ovary syndromeHuman Reproduction
Current Pharmaceutical Design
Mediators of Low-Grade Chronic Inflammation in Polycystic Ovary Syndrome (PCOS)
Current Pharmaceutical Design, 19():
Gynecological EndocrinologyThe role of cytokines in polycystic ovarian syndromeGynecological Endocrinology
Birth Defects Research Part B-Developmental and Reproductive ToxicologyThe Effects of Interleukin-6 Signal Blockade on Immune System, Reproductive and Skeletal Development in Juvenile MiceBirth Defects Research Part B-Developmental and Reproductive Toxicology
Przeglad MenopauzalnyBiological role of tumor necrosis factor type a in physiology and pathophysiologyPrzeglad Menopauzalny
Current Opinion in Obstetrics and GynecologyBariatric surgery and fertilityCurrent Opinion in Obstetrics and Gynecology
© 2003 The American College of Obstetricians and Gynecologists