Revista Societatii de Medicina Interna

Articolul face parte din revista :
  Nr.1 din luna martie 2011

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Petríková Jana

Titlu articol

POLYCYSTIC OVARY SYNDROME AND AUTOIMMUNITY

Cuvinte cheie

sindromul ovarelor polichistice, autoimunitate, autoanticorpi, hiperandrogenism.

Articol

Polycystic ovary syndrome is one of the most common endocrinopaties among women of childbearing age and cause of infertility. This syndrome was described by Stein and Leventhal in 1935(1), although the presence of sclerocystic ovaries had been recognized for at least 90 years before the publication of that seminal work. The prevalence is around 6.5-8 %(2) affecting 1 in 13–15 unselected women. There are five million affected women in the US and 105 million worldwide. The polycystic ovary syndrome is characterized by chronic oligoovulatory/anovulatory state, hyperandrogenism and polycystic ovaries on ultrasound vaginal examination. Revised diagnostic criteria have been proposed based upon a 2003 consensus meeting held in Rotterdam. In the revised criteria, two out of three of the following are required to make the diagnosis:

•  Oligo- and/or anovulation;
•  Clinical and/or biochemical signs of hyperandrogenism;
•  Polycystic ovaries (by ultrasound)(3).

It is well accepted to exclude also others etiologies of hyperandrogenism (congenital adrenal hyperplasia, androgen-secreting tumors, Cushing s syndrome) prior to diagnosis of PCOS. The prevalence of PCOS was found to be increased in women who developed premature adrenarche(4), gestational diabetes(5, 6), and in those with first-degree relatives with PCOS(7, 8). Several conditions were also associated with increased prevalence of PCOS including obesity, insulin resistance(9, 10), type 2 diabetes mellitus (DM)(11, 12) and endometrial carcinoma due to prolonged estrogen stimulation unopposed by progesterone(13). Additionally, higher risk of cardio-vascular diseases among these patients has been described(14). Dejager et al.(15) described 13-fold higher risk of acute myocardial infarction.

PCOS and autoimmunity

1. Immune dysregulation in PCOS - cause or effect?
The state of estrogens excess has been linked to different autoimmune diseases. This was confirmed by studies on women of reproductive age, which showed higher prevalence of systemic autoimmune diseases(16) as well as studies in hypogonadal men having relative excess of estrogens. For example in patients with Klinefelter syndrome an association with rheumatic and autoimmune diseases has been reported particularly with rheumatoid arthritis, juvenile idiopathic arthritis, psoriatic arthritis, polymyositis/dermatomyositis, systemic lupus erythematosus (SLE), systemic sclerosis, mixed connective tissue disease, antiphospholipid syndrome and others(17). In another study a correlation between Klinefelter syndrome and rare autoimmune diseases such as primary biliary cirrhosis was suggested(18). High levels of androgens are presented in patients who suffer from PCOS seeming to have a protective role against the development of autoimmune disease, however several mechanisms related to estrogen effects on the immune system oppose these activity. Estrogens increase the secretion of IL-4 in Th2 lymphocytes, IL-1 in monocytes, IL-6 in T-lymphocytes and interferone-γ in Th1 cells. During normal ovulatory menstrual cycle in young women – follicular phase is characterized by elevation of IL-6 whereas its levels are decreased in the luteal phase which is also characterized by negative correlation with progesterone(19). The stimulatory effect of estrogens on the immune system could be inhibited by progesterone. Patients with PCOS present low level of progesterone due to oligo/anovulation therefore the immune system could be over-stimulated leading to production of autoantibodies in these patients.
In addition the role of vitamin D in regulations of immune mechanism has been described. In a study of 206 PCOS women, 72,8% were found to be with 25 (OH) vitamin D insufficiency (<30 ng/ml). These women had significantly worse metabolic characteristics in comparison with those who present a sufficient 25 (OH) vitamin D levels(20). Although this study has limitations of not including control group and women with metabolic syndrome but without PCOS, large intervention trials might be needed to evaluate the effect of vitamin D supplementation on metabolic disturbances in PCOS women. The hypothesis that vitamin D relates to autoimmune disorders emerged from the observation that people living near the equator were at a decreased risk of developing common autoimmune diseases(21).
Obesity is a risk factor for lower levels of vitamin D, as this vitamin is stored in fat(22). Between 30% and 47% of patients with PCOS have the metabolic syndrome and obesity. Especially central obesity, insulin resistance, and dyslipidemia are also associated with chronic inflammation and rheumatic diseases(23,24). Furthermore, several surveys of rheumatology populations found reduced levels of vitamin D. In a study of Orbach et al.(25) 1029 patients with different autoimmune disorders including scleroderma, polymyositis and dermatomyositis, antiphospholipid syndrome, rheumatoid arthritis and SLE had lower levels (average of 9,3 – 13,7 ng/mL) of 25(OH)D than controls.

2. Association of PCOS with autoimmune disorders
  PCOS and non-organ specific autoimmunity
Recently few studies addressed the association between PCOS and autoimmunity with controversial results. Hefler-Frischmuth et al. evaluated 109 sera from PCOS patients and performed anti-nuclear antibodies (ANA) screen, anti-histone, anti-nucleosome, and the anti ds-DNA utilizing ELISA tests. Statistical significance (p<0,05) was found only in the levels of anti-histone and anti-dsDNA antibodies(26). In another study, 36 PCOS patients were evaluated for smooth muscle cell (SMA), liver-kidney microsome (LKMA), thyroid microsome (TMA), gastric parietal cell (PCA), ANA, reticulin (ARA) and mitochondrial antibodies (AMA) using indirect immunoflourescence method(27). Significant difference in detection of ANA and SMA was found in 7 PCOS patients (19,4 %) versus 3,6 and 5,1 % incidence in control group of 392 women respectively (p<0,005). The rest of antibodies were negative. The difference in ANA levels between these studies might be explained by using distinct methods. Other autoimmune diseases were reported in association with sexual dimorphism such as systemic lupus erythematosus and estrogen influence(28).

  PCOS and organ specific autoimmunity
High prevalence of autoimmune thyroiditis (AIT) was documented in a study of 175 patients with PCOS. Thyroid function and thyroid specific antibody tests revealed elevated thyroperoxidase (TPO) or thyroglobulin (TG) antibodies in 14 of 168 controls (8.3%), and in 47 of 175 patients with PCOS (26.9%) (p<0•001). On thyroid ultrasound 42.3% of PCOS patients had a hypoechogenic tissue typical for AIT, in contrast to only 6.5% of the control group (p<0•001). While thyroid hormone levels were normal in all subjects, PCOS patients had a higher mean thyrotropin (TSH) level and a higher incidence of TSH levels above the upper limit of normal (PCOS 10.9%, controls 1.8%) (p<0•001)(29). A case report was published of a patient with autoimmune polyglandular syndrome type II and PCOS: 26-years old woman was diagnosed with: (1) type 1 diabetes, with hyperglycemia, impaired insulin secretion, and positive autoantibodies for GAD-65 and IA-2; (2) autoimmune thyroiditis, with hypothyroidism, positive anti-microsomal and anti-thyroglobulin antibodies; and (3) PCOS, with hyperandrogenic signs that had developed 5 years earlier(30). Recent study on 50 pregnant PCOS patients and 59 normal pregnancies in Chilean women showed no association between anti-GAD65 and anti-IA2 auto-antibodies (2.0% and 1.7%, respectively) known in DM(31).
Studies of anti-ovarian antibodies that were performed so far yielded conflicting results. Evaluation of antibodies directed at human ovary using ELISA resulted in mean ratios which were significantly higher for women with PCOS than for the control group (figure: IgG (p<0•0001), IgA (p<0•003), IgM (p<0•0003). Positive anti-ovarian antibodies for at least one isotype were present in 15 (44%) of 34 of the PCOS (32) women: IgG in nine patients (27%), IgA one (3%) and IgM nine (27%), respectively. However these results could not be confirmed by others(33,34). A significant correlation between levels of antiovarian antibodies and cycles of in vitro fertilization was found. Repeated punctures of ovarian tissue and microtraumatic changes may reveal ovarian antigens so far unknown for immune system and induce a response(35). On the other hand detection of anti-ovarian antibodies after laparoscopic electrocauterization in treatment of PCOS patients resistant to clomiphene citrate did not show higher rates compared to pre-operation state(36). Suh reported histological findings in a case of PCOS consistent with autoimmune oophoritis(37). Lonsdale et al. demonstrated ovarian and adrenal antibodies, and lymphocytic infiltration of ovaries in two patients with PCOS(38). van Gelderen and Gomes dos Santos showed antibodies to human ovarian sections and granulosa cells by immunofluorescence in 4/8 patients with PCOS(39). Anti-FSH antibodies of the IgA class specifically against the ß chain of FSH were significantly higher among 75 PCOS patients compared with 85 healthy controls(40). Another theory suspects a role of oxidative stress as a key in the development of PCOS. Free radicals may harm reproductive cells, early stages of embryonic development or even endometrial cells. In a group of 10 patients with PCOS a significant elevation of anti-endometrial antibodies detected by ELISA has been published as well as antibodies against malondialdehyde modified human serum albumin compared to 21 controls with male factor of infertility(41). A key study in this field was performed by Chapman et al., showing fundamental role of estrogen induced immune disruption of thymus in the development of PCOS in animal model. Naïve mice were injected with estrogen after removing thymus gland. Anovulation and follicular cysts formation occurred subsequently. In contrary, no cysts were observed in mice in which thymectomy at 3 days of age preceded estrogen injection. In fact, after restoring immune function by thymocyte replacement, the majority of thymectomized, estrogen-injected mice had ovaries with corpora lutea. In conclusion, when estrogen was not able to act on thymus, no cysts developed and mice had ovulation.Subsequent research showed that the disease is transferable by lymfocyte infusion fulfilling another condition of autoimmune diseases.  Absence of regulatory T cells seemed crucial for developing ovarian cysts(42). Gleicher et al. claims PCOS might be an opposite condition to premature ovarian failure (POF), which in contrast is a state characterized by the loss of ovarian functions before the age of 40; its prevalence is ~1% of women. They suppose that functional autoantibodies play an important role in pathogenesis of both diseases(43). Classically, POF has a genetic, enzymatic, infectious, or iatrogenic etiology(44,45). POF is considered as an immunological disease, and has been suggested for a long time to be associated with several factors, including autoimmune disease(46,47), ovarian lymphocytic infiltration(48), detection of anti-ovarian antibodies(49,50) and reversibility of ovarian function with high doses of glucocorticoids immunotherapy(51).

Conclusion

The polycystic ovary syndrome is one of the most common hormonal disorders affecting women. As a syndrome, it has multiple components — reproductive, metabolic, and cardiovascular — with health implications throughout life. In the field of obstetrics and gynecology several conditions such as preeclampsia(53), recurrent miscarriage(54,55), endometriosis(56), fibroids(57), several malignant tumors(58), and ovarian diseases such as POF, have been shown to be associated with autoimmunologic processes. The human ovary can be the target of an autoimmune attack in various circumstances, including several organ-specific or systemic autoimmune diseases. Clinically, the ensuing ovarian dysfunction often results in POF, but other pathologies involving the ovaries, such as unexplained infertility, PCOS and endometriosis have been associated with antiovarian autoimmunity(59). Regarding PCOS, studies on autoimmunity yielded conflicting results. Whether or not women with PCOS are at an increased risk for developing rheumatologic diseases is unknown and should be investigated in future trials. So far, it was proven that an AIT has higher incidence among women with PCOS. Thus, the prevalence of systemic and organ specific autoantibodies as well as their clinical significance in PCOS remains to be elucidated and it is important to continue to explore mechanisms by which autoimmune diseases can be related to PCOS. 

References
1.    Stein IF, Leventhal NL. Amenorrhea associated with bilateral polycystic ovaries. Am J Obstet Gynecol 1935; 29: 181–191.
2.    Asuncion M, Calvo RM, San Millán JL, Sancho J, Avila S, Escobar-Morreale HF. A prospective study of the prevalence of the polycystic ovary syndrome in unselected Caucasian women from Spain. J Clin Endocrinol Metab 2000, 85: 2434–2438.
3.    Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome (PCOS). Hum Reprod 2004; 19:41.
4.    Ibañez L, Dimartino-Nardi J, Potau N, Saenger P. Premature adrenarche – normal variant or forerunner of adult disease? Endocr Rev 2000; 21: 671–696.
5.    Anttila L, Karjala K, Penttilä RA, Ruutiainen K, Ekblad U. Polycystic ovaries in women with gestational diabetes. Obstet Gynecol 1998; 92: 13–6.
6.    Holte J, Gennarelli G, Wide L, Lithell H, Berne C. High prevalence of polycystic ovaries and associated clinical, endocrine, and metabolic features in women with previous gestational diabetes mellitus. J Clin Endocrinol Metab 1998; 83: 1143–1150.
7.    Legro RS, Driscoll D, Strauss JF 3rd, Fox J, Dunaif A. Evidence for a genetic basis for hyperandrogenemia in polycystic ovary syndrome. Proc Natl Acad Sci USA 1998; 95: 14956–14960.
8.    Kahsar-Miller M, Nixon C, Boots LR, Go RC, Azziz R. Prevalence of the polycystic ovary syndrome (PCOS) among first degree relatives of patients with PCOS. Fertil Steril 2001; 75: 53–58.
9.    DeUgarte CM, Bartolucci AA, Azziz R. Prevalence of insulin resistance in the polycystic ovary syndrome using the homeostasis model assessment. Fertil Steril 2005; 83: 1454–1460.
10.    Legro RS, Finegood D, Dunaif A. A fasting glucose to insulin ratio is a useful measure of insulin sensitivity in women with polycystic ovary syndrome. J Clin Endocrinol Metab 1998; 83: 2694–2698.
11.    Legro RS, Kunselman AR, Dodson WC, Dunaif A. Prevalence and predictors of risk for type 2 diabetes mellitus and impaired glucose tolerance in polycystic ovary syndrome: a prospective, controlled study in 254 affected women. J Clin Endocrinol Metab 1999; 84: 165–169.
12.    Ehrmann DA, Kasza K, Azziz R, Legro RS, Ghazii MN. Effects of race and family history of type 2 diabetes on metabolic status of women with polycystic ovary syndrome. J Clin Endocrinol Metab 2005; 90: 66–71.
13.    Hardiman P, Pillay OS, Atiorno W. Polycystic ovary syndrome and endometrial carcinoma. Lancet 2003; 361: 1810–1812.
14.    Legro RS. Polycystic ovary syndrome and cardiovascular disease: a premature association? Endocrine Rev 2003; 24: 302–312.
15.    Dejager S, Pichard C, Giral P, Bruckert E, Federspield MC, Beucler I et al. Smaller LDL particle size in women with polycystic ovary syndrome compared to controls. Clin Endocrinol 2001; 54: 455–462.
16.    Lahita RG. Gender disparity in systemic lupus erythematosus, thoughts after the 8th International Congress on Systemic Lupus Erythematosus, Shanghai, China, 2007. J Clin Rheumatol. 2008; 14(3): 185-187.
17.    Rovenský J, Imrich R, Lazúrová I, Payer J. Rheumatic Diseases and Klinefelter s Syndrome. Ann New York Acad Sci 2009; accepted for publish
18.    Li J, Su JM, Zeng XJ. Is primary biliary cirrhosis another example of an immunemediated complication of Klinefelter syndrome? J Clin Rheumatol 2004; 10: 286-287.
19.    Angstwurm MW, Gartner R, Ziegler-Heitbrock HW. Cyclic plasma IL-6 levels during normal menstrual cycle. Cytokine 1997; 9: 370–374.
20.    Wehr E, Pilz S, Schweighofer N, Giuliani A, Kopera D, Pieber TR et al. Interaction of 25-hydroxyvitamin D levels with metabolic characteristics in polycystic ovary syndrome. Bone 2009; 44: 357-358.
21.    Holick MF. Vitamin D: A millenium perspective. J Cell Biochem 2003; 88: 296-307.
22.    Zittermann A. Vitamin D in preventive medicine: are we ignoring the evidence? Br J Nutr 2003; 89: 552-572.
23.    Escárcega RO, García-Carrasco M, Fuentes-Alexandro S, Jara LJ, Rojas-Rodriquez J, Escobar-Linares LE et al. Insulin resistance, chronic inflammatory state and the link with systemic lupus erythematosus-related coronary disease. Autoimmun Rev 2006; 6: 48-53.
24.    Dessein PH, Joffe BI. Insulin resistance and impaired beta cell functions in reumathoid arthritis. Arthritis Rheum 2006; 54: 2765-75.
25.    Orbach H, Zandman-Goddard G, Amital H, Barak V, Szekanecz Z, Szucs G et al. Novel biomarkers in autoimmune diseases: prolactin, ferritin, vitamin D, and TPA levels in autoimmune diseases. Ann N Y Acad Sci 2007;1109:385-400.
26.    Hefler-Frischmuth K, Walch K, Huebl W, Baumuehlner K, Tempfer C, Hefler L. Serologic markers of autoimmunity in women with the polycystic ovary syndrome. Fertil Steril 2009; 92 (5): 60.
27.    Reimand K, Talja I, Metskűla K, Kadastik U, Matt K, Uibo R. Autoantibody studies of female patients with reproductive failure. J Reprod Immunol 2001; 51: 167–176.
28.    Lahita RG. The role of sex hormones in systemic lupus erythematosus. Curr Opin Rheumatol 1999; 11: 352–356.
29.    Janssen OE, Mehlmauer N, Hahn S, Offner AH, Gärtner R. High prevalence of autoimmune thyroiditis in patients with polycystic ovary syndrome. Eur J Endocrinol 2004; 150: 363–369.
30.    Lee SH, Kim MR, Kim JH, Kwon HS, Yoon KH, Son HY et al. A patient with combined polycystic ovary syndrome and autoimmune polyglandular syndrome type 2. Gynecol Endocrinol 2007; 23: 252–256.
31.    Pérez-Bravo F, Carrasco E, Echiburú B, Maliqueo M, Diaz J, Sir-Petermann T. Serological markers of autoimmunity in pregnant women with polycystic ovary syndrome: a pilot study. Gynecol Endocrinol 2010; 26(12):889-93.
32.    Fénichel P, Gobert B, Carré Y, Barbarino-Monnier P, Hiéronimus S. Polycystic ovary syndrome in autoimmune disease. Lancet 1999; 353: 2210.
33.    Rojanski N, Roll D, Meirow D. Polycystic ovary syndrome. An autoimmune disease? J Reprod Med 1997; 42: 325-328.
34.    Luborsky JL, Shatavi S, Adamczyk P, Chiong C, Llanes B, Lafniztzegger J et al. Polycystic ovary syndrome and ovarian autoimmunity - assessment of ovarian antibodies by EIA. J Reprod Immunol 1999; 42: 79-84.
35.    Gobert B, Barbarino-Monnnier P, Guillet-Rosso F, Bene MC,Faure GC. Anti-ovary antibodies after attempts at human in vitro fertilization induced by follicular puncture rather than hormonal stimulation. J Reprod Fertil 1992; 96 : 213 – 21.
36.    Alborzi S, Tavazoo F, Dehaghani AS, Ghaderi A, Alborzi S, Alborzi M. Determination of antiovarian antibodies after laparoscopic ovarian electrocauterization in patients with polycystic ovary syndrome. Fertil Steril 2009; 91(4):1159-63.
37.    Suh Y. Autoimmune oophoritis—a case report. J Korean Med Sci 1992; 7: 284–290.
38.    Lonsdale RN, Roberts PF, Trowell JE. Autoimmune oophoritis associated with polycystic ovaries. Histopathol 1991; 19: 77–81.
39.    van Gelderen CJ and Gomes dos Santos ML. Polycystic ovarian syndrome. Evidence for an autoimmune mechanism in some cases. J Reprod Med 1993; 38: 381–386.
40.    Haller K, Mathieu Ch, Rull K, Matt K, Béné MC, Uibo R. IgG, IgA and IgM Antibodies against FSH: Serological Markers of Pathogenic Autoimmunity or of Normal Immunoregulation? Am J Reprod Immunol 2005; 54: 262-269.
41.    Palacio JR, Iborra A, Ulcova-Gallova Z, Badia R, Martínez P. The presence of antibodies to oxidative modified proteins in serum from polycystic ovary syndrome patients. Clin Exp Immunol 2006; 144: 217-222.
42.    Chapman JC, Min SH, Freeh SM, Michael SD. The estrogen-injected female mouse: new insight into the etiology of PCOS. Reprod Biol Endocrinol. 2009; 18;7:47.
43.    Gleicher N, El-Roeiy A, Confino E, Friberg J. Is endometriosis an autoimmune disease? Obstet Gynecol 1987; 70: 115-122.
44.    Anasti JN. Premature ovarian failure: an update. Fertil Steril 1998; 70:1-15.
45.    Kalantaridou SN, Davis SR and Nelson LM. Premature ovarian failure. Endocrinol Metab Clin North Am 1998; 27: 989-1006.
46.    Irvine WJ, Cahn MW, Scarth L, Kolb FO, Hartog M, Bayliss RI et al. Immunological aspects of premature ovarian failure associated with Addison s disease. Lancet 1968;  2 (7574): 883-887.
47.    Vasquez AM, Kenny FM. Ovarian failure and antiovarian antibodies in association with hypoparathyroidism, moniliasis, and Addison s and Hashimoto s disease. Obstet Gynecol 1973; 41: 3.
48.    Tung KSK, Lu CY. Immunological basis of reproductive failure. In Krans, F.T., Danijanov, I. and Kaufman, N. (eds). Pathology of Reproductive Failure 1991. Williams & Wilkins, Baltimore, pp. 308–333.
49.    Luborsky JL, Visintin I, Boyers S, Asari T, Caldwell B, DeCherney A. Ovarian antibodies detected by immobilized antigen immunoassay in patients with premature ovarian failure. J Clin Endocrinol Metab 1990; 70: 69–75.
50.    Wheatcroft NJ, Toogood AA, Li TC, Cooke ID, Weetman AP. Detection of antibodies to ovarian antigens in women with premature failure. Clin Exp Immunol 1994; 96: 122–128.
51.    Corenblum B, Rowe T, Taylor PJ. High doses, short term glucocorticoids for the treatment of infertility resulting from premature ovarian failure. Fertil. Steril 1993; 59: 988–991.
52.    Laven JS, Imani B, Eijkemans MJ, Fauser BC. New approaches to PCOS and other forms of anovulation. Obstet Gynecol Surv 2002; 57: 755–767.
53.    Xia Y, Zhou CC, Ramin SM, Kellems RE. Angiotensin receptors, autoimmunity, and preeclampsia. J Immunol 2007; 15;179(6): 3391-5.
54.    Cervera R, Balasch J. Autoimmunity and recurrent pregnancy losses. Clin Rev Allergy Immunol. 2009; in press
55.    Konova E, Aleksovska T, Atanasova M, Georgieva M, Todorova K, Lukanov T et al. Anti-elastin antibodies and elastin turnover in normal pregnancy and recurrent pregnancy loss. Am J Reprod Immunol 2009; 61(2): 167-174.
56.    Matarese G, De Placido G, Nikas Y, Alviggi C. Pathogenesis of endometriosis: natural immunity dysfunction or autoimmune disease? Trends Mol Med 2003; 9: 223–228.
57.    Hsieh YY, Chang CC, Tsai FJ, Lin CC, Yeh LS, Tsai CH. Tumor necrosis factor-alpha-308 promoter and p53 codon 72 gene polymorphisms in women with leiomyomas. Fertil Steril 2004; 82: 1177–1181.
58.    Barber HR. Present status of tumor immunology in clinical gynecology. Am J Reprod Immunol 1989; 20: 140–146.
59.    Luborsky JL, Thiruppathi P, Rivnay B, Roussev R, Coulam C, Radwanska E.  Evidence for different aetiologies of low estradiol response to FSH: age-related accelerated luteinization of follicles or presence of ovarian antibodies? Hum Reprod 2002; 17: 2641-2649.