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Polycystic o vary syndrome in autoimmune disease
RESEARCH LETTERS
Polycystic o var y syndrome in autoimmune disease Patrick Fénichel, Bernard Gobert, Yves Carré, Patricia Barbarino-Monnier, Sylvie Hiéronimus
Polycystic ovary syndrome (PCOS), the most frequent endocrine disorder in women, is characterised by a chronic hyperandrogenic and anovulatory state. Several mechanisms, including high concentrations of luteinising hormone, hyperinsulinaemia, and ovarian 17␣ hydroxylase d y s r e g u l a t i o n1 have been proposed to explain hyperstimulation of the ovarian thecal and stromal cells and folliculogenesis impairment. Nevertheless, pathogenesis of this syndrome is debated.1 To find out whether an autoimmune reaction could contribute to the ovarian dysfunction of PCOS, we assayed circulating antiovarian antibodies in 34 anovulatory women (mean age 23·5 years [SD 4·7]) with clinical hyperandrogenia (88%), body-mass index more than 28 kg/m 2 (50%), raised plasma andogens (59%), luteinising hormone (58%), or both, and polymicrocystic ovaries with stromal hypertrophy on ultrasonography (50%). Results of circulating antiovarian antibody isotypes assessed with ELISA with human ovary as antigen, 2 were expressed as the ratio of the optical density of each serum to that of a standard serum. The reference optical density was equivalent to the mean plus 2 SDs of that obtained by the reduced-variable method from normal healthy controls (17 men and 23 women in the same age range without any autoimmune disease or fertility disorder).2 Values higher than one were taken to be positive. Mean ratios 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 antiovarian antibodies for at least one isotype were present in 15 (44%) of 34 of the PCOS women: IgG nine (27%), IgA one (3%), IgM nine (27%). The specificity of these antiovarian antibodies was assessed by comparing PCOS group with a Grave’s disease group (n=35) as negative control, and with a spontaneous premature-ovarian-failure group3 of 46 women as positive control. High concentrations of antiovarian antibody found in a group of PCOS suggest that an immune reaction is associated to PCOS. With the same ELISA, high concentrations of antiovarian antibody have been detected
after in-vitro fertilisation cycles 2 or in the case of premature ovarian failure.3 In the first case, microtrauma of repeated ovarian punctures seemed to induce the production of local and systemic autoantibodies 2 by externalisation of differentiation antigens. In the second case, familial, personal, or both autoimmune diseases were frequently associated.3 None of our patients with PCOS had, however, undergone surgery, ovarian biopsy, in-vitro-fertilisation punction, or ovulation induction and in none was PCOS associated with autoimmune disease. Ovarian cells of the white-cell series and cytokines have been reported to participate to the regulation of folliculogenesis. 4 Dexamethasone, a synthetic corticosteroid, has been shown to improve ovulation induction in PCOS, through a suggested endocrine effect. 5 Dexamethasone can modify directly follicular cytokine concentrations such as tumour necrosis factor ␣.5 Production of antiovarian antibody in PCOS may be related to an inflammatory reaction with abnormal production of cytokines 5 and overexpression of class II antigens. The potential role and prognostic value concerning anovulation of such a paradoxical production of antiovarian antibody in PCOS need to be assessed. 1
Homburg R. Polycystic ovary syndrome: from gynaecological curiosity to multisystem endocrinopathy. Hum Reprod 1996; 1 1 : 29–39. 2 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; 9 6 : 213–21. 3 Fénichel P, Sosset C, Barbarino-Monnier P, et al. Prevalence, specificity and significance of antiovarian antibodies during spontaneous premature ovarian failure. Hum Reprod 1997; 1 2 : 2623–28. 4 Brännström M, Norman RJ. Involvement of leucocytes and cytokines in the ovulatory process and corpus luteum function. Hum Reprod 1993; 8 : 1762–75. 5 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; 5 7 : 501–04.
Service d’Endocrinologie et Médecine de la Reproduction, Centre Hospitalo-Universitaire de Nice, Nice 06202, France (Prof P Fénichel); and Laboratoire d’Immunologie, Centre Hospitalo-Universitaire de Nancy, Vandoeuvre les Nancy, France
Increase in sepsis due to multiresistant enteric gram-negative bacilli in Papua New Guinea Trevor Duke, Audrey Michael
Circulating antiovary antibodies (mean ratios [SD]) in PCOS *p <0·003.
2210
WHO recommends ampicillin (or benzylpenicillin) and gentamicin as empirical treatment of sepsis or pneumonia in children under age 2 months in developing countries. 1 For children older than 2 months with very severe pneumonia, WHO recommends chloramphenicol. 1 There are limited data on the incidence of chloramphenicolresistant and gentamicin-resistant sepsis in rural hospitals in developing countries. In 1984, studies from Goroka Hospital, which serves a large rural area in the highlands of Papua New Guinea, found enteric gram-negative bacilli to be a rare cause of pneumonia or sepsis in children.2,3 In mid-1997, after finding several neonates with multiresistant Klebsiella sepsis, we began a prospective study to determine the incidence of antibiotic-resistant gram-negative sepsis and their effect on mortality in children at Goroka Hospital. In children with severe sepsis, and in those who deteriorated despite standard antibiotic treatment, cultures of blood, cerebrospinal fluid (CSF), lung aspirate, and other suspected infected sites were done. In children who
THE LANCET • Vol 353 • June 26, 1999
Polycystic o var y syndrome in autoimmune disease Patrick Fénichel, Bernard Gobert, Yves Carré, Patricia Barbarino-Monnier, Sylvie Hiéronimus
Polycystic ovary syndrome (PCOS), the most frequent endocrine disorder in women, is characterised by a chronic hyperandrogenic and anovulatory state. Several mechanisms, including high concentrations of luteinising hormone, hyperinsulinaemia, and ovarian 17␣ hydroxylase d y s r e g u l a t i o n1 have been proposed to explain hyperstimulation of the ovarian thecal and stromal cells and folliculogenesis impairment. Nevertheless, pathogenesis of this syndrome is debated.1 To find out whether an autoimmune reaction could contribute to the ovarian dysfunction of PCOS, we assayed circulating antiovarian antibodies in 34 anovulatory women (mean age 23·5 years [SD 4·7]) with clinical hyperandrogenia (88%), body-mass index more than 28 kg/m 2 (50%), raised plasma andogens (59%), luteinising hormone (58%), or both, and polymicrocystic ovaries with stromal hypertrophy on ultrasonography (50%). Results of circulating antiovarian antibody isotypes assessed with ELISA with human ovary as antigen, 2 were expressed as the ratio of the optical density of each serum to that of a standard serum. The reference optical density was equivalent to the mean plus 2 SDs of that obtained by the reduced-variable method from normal healthy controls (17 men and 23 women in the same age range without any autoimmune disease or fertility disorder).2 Values higher than one were taken to be positive. Mean ratios 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 antiovarian antibodies for at least one isotype were present in 15 (44%) of 34 of the PCOS women: IgG nine (27%), IgA one (3%), IgM nine (27%). The specificity of these antiovarian antibodies was assessed by comparing PCOS group with a Grave’s disease group (n=35) as negative control, and with a spontaneous premature-ovarian-failure group3 of 46 women as positive control. High concentrations of antiovarian antibody found in a group of PCOS suggest that an immune reaction is associated to PCOS. With the same ELISA, high concentrations of antiovarian antibody have been detected
after in-vitro fertilisation cycles 2 or in the case of premature ovarian failure.3 In the first case, microtrauma of repeated ovarian punctures seemed to induce the production of local and systemic autoantibodies 2 by externalisation of differentiation antigens. In the second case, familial, personal, or both autoimmune diseases were frequently associated.3 None of our patients with PCOS had, however, undergone surgery, ovarian biopsy, in-vitro-fertilisation punction, or ovulation induction and in none was PCOS associated with autoimmune disease. Ovarian cells of the white-cell series and cytokines have been reported to participate to the regulation of folliculogenesis. 4 Dexamethasone, a synthetic corticosteroid, has been shown to improve ovulation induction in PCOS, through a suggested endocrine effect. 5 Dexamethasone can modify directly follicular cytokine concentrations such as tumour necrosis factor ␣.5 Production of antiovarian antibody in PCOS may be related to an inflammatory reaction with abnormal production of cytokines 5 and overexpression of class II antigens. The potential role and prognostic value concerning anovulation of such a paradoxical production of antiovarian antibody in PCOS need to be assessed. 1
Homburg R. Polycystic ovary syndrome: from gynaecological curiosity to multisystem endocrinopathy. Hum Reprod 1996; 1 1 : 29–39. 2 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; 9 6 : 213–21. 3 Fénichel P, Sosset C, Barbarino-Monnier P, et al. Prevalence, specificity and significance of antiovarian antibodies during spontaneous premature ovarian failure. Hum Reprod 1997; 1 2 : 2623–28. 4 Brännström M, Norman RJ. Involvement of leucocytes and cytokines in the ovulatory process and corpus luteum function. Hum Reprod 1993; 8 : 1762–75. 5 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; 5 7 : 501–04.
Service d’Endocrinologie et Médecine de la Reproduction, Centre Hospitalo-Universitaire de Nice, Nice 06202, France (Prof P Fénichel); and Laboratoire d’Immunologie, Centre Hospitalo-Universitaire de Nancy, Vandoeuvre les Nancy, France
Increase in sepsis due to multiresistant enteric gram-negative bacilli in Papua New Guinea Trevor Duke, Audrey Michael
Circulating antiovary antibodies (mean ratios [SD]) in PCOS *p <0·003.
2210
WHO recommends ampicillin (or benzylpenicillin) and gentamicin as empirical treatment of sepsis or pneumonia in children under age 2 months in developing countries. 1 For children older than 2 months with very severe pneumonia, WHO recommends chloramphenicol. 1 There are limited data on the incidence of chloramphenicolresistant and gentamicin-resistant sepsis in rural hospitals in developing countries. In 1984, studies from Goroka Hospital, which serves a large rural area in the highlands of Papua New Guinea, found enteric gram-negative bacilli to be a rare cause of pneumonia or sepsis in children.2,3 In mid-1997, after finding several neonates with multiresistant Klebsiella sepsis, we began a prospective study to determine the incidence of antibiotic-resistant gram-negative sepsis and their effect on mortality in children at Goroka Hospital. In children with severe sepsis, and in those who deteriorated despite standard antibiotic treatment, cultures of blood, cerebrospinal fluid (CSF), lung aspirate, and other suspected infected sites were done. In children who
THE LANCET • Vol 353 • June 26, 1999