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High Frequency of Association of Rheumatic/Autoimmune Diseases Available online http://arthritis-research.com/content/3/6/362 Research article High frequency of association of rheumatic/autoimmune diseases and untreated male hypogonadism with severe testicular dysfunction F Javier Jiménez-Balderas*, Rosario Tápia-Serrano†, M Eugenia Fonseca‡, Jorge Arellano§, Arturo Beltrán*, Patricia Yáñez*, Adolfo Camargo-Coronel* and Antonio Fraga* *Departmento de Reumatología, Hospital de Especialidades, Centro Médico Nacional SXXI IMSS México, DF, México †Sección de Andrología, Hospital de Especialidades, Centro Médico Nacional SXXI IMSS México, DF, México ‡Laboratorio de Hormonas, Hospital de Especialidades, Centro Médico Nacional SXXI IMSS México, DF, México §Unidad de Investigación Médica en Inmunología, Hospital de Pediatría, Centro Médico Nacional SXXI IMSS México, DF, México Correspondence: F Javier Jiménez-Balderas MD, Pregonero #161, Col Fraccionamiento Colina del Sur, CP 01430, México, DF, México. Tel: +52 5 627 69 00, ext 13-15; fax: +52 5 584 00 89; e-mail: [email protected] Received: 10 January 2001 Arthritis Res 2001, 3:362-367 Revisions requested: 16 March 2001 This article may contain supplementary data which can only be found Revisions received: 25 July 2001 online at http://arthritis-research.com/content/3/6/362 Accepted: 7 August 2001 © 2001 Balderas et al, licensee BioMed Central Ltd Published: 12 September 2001 (Print ISSN 1465-9905; Online ISSN 1465-9913) Abstract Our goal in the present work was to determine whether male patients with untreated hypogonadism have an increased risk of developing rheumatic/autoimmune disease (RAD), and, if so, whether there is a relation to the type of hypogonadism. We carried out neuroendocrine, genetic, and rheumatologic investigations in 13 such patients and 10 healthy male 46,XY normogonadic control subjects. Age and body mass index were similar in the two groups. Nine of the 13 patients had hypergonadotropic hypogonadism (five of whom had Klinefelter’s syndrome [karyotype 47,XXY]) and 4 of the 13 had hypogonadotropic hypogonadism (46,XY). Of these last four, two had Kallmann’s syndrome and two had idiopathic cryptorchidism. Eight (61%) of the 13 patients studied had RADs unrelated to the etiology of their hypogonadism. Of these, four had ankylosing spondylitis and histocompatibility B27 antigen, two had systemic lupus erythematosus (in one case associated with antiphospholipids), one had juvenile rheumatoid arthritis, and one had juvenile dermatomyositis. In comparison with the low frequencies of RADs in the general population (about 0.83%, including systemic lupus erythematosus, 0.03%; dermatomyositis, 0.04%; juvenile rheumatoid arthritis, 0.03%; ankylosing spondylitis, 0.01%; rheumatoid arthritis, 0.62%; and other RAD, 0.1%), there were surprisingly high frequencies of such disorders in this small group of patients with untreated hypogonadism (P < 0.001) and very low serum testosterone levels (P = 0.0005). The presence of RADs in these patients was independent of the etiology of their hypogonadism and was associated with marked gonadal failure with very low testosterone levels. Keywords: ankylosing spondylitis, hypogonadism, rheumatic diseases, systemic lupus erythematosus, testosterone Introduction autoimmune diseases in females and an increased The clinical observation that sexual dimorphism plays a immune response to antigenic stimulus. These observa- role in the immune response suggests that the endocrine tions make it evident that sexual dimorphism probably acts system is an important factor for the development and on the immune response through its effect upon the maintenance of the response. There is a high frequency of thymic–hypothalamic–pituitary–gonadic axis [1]. AS = ankylosing spondylitis; B27 = histocompatibility antigen B27; CREST = calcinosis, Raynaud's phenomenon, esophageal dysfunction, sclero- β dactyly, telangiectasia; E2 = estradiol-17 ; JRA = juvenile rheumatoid arthritis; RA = rheumatoid arthritis; RAD = rheumatic/autoimmune disease; SLE = systemic lupus erythematosus. Available online http://arthritis-research.com/content/3/6/362 Series of subjects with gonadal dysgenesis, and isolated phenomenon, esophageal dysfunction, sclerodactyly, cases of Klinefelter’s syndrome associated with telangiectasia), and Behçet’s syndrome [22]. Venous rheumatic/autoimmune diseases (RAD), suggest a relation blood (20 ml) was extracted to determine the erythrocyte between these clinical conditions [2,3]. Among male sedimentation rate (Wintrobe method, mm/h), lupus ery- patients reported to date who have hypogonadism and thematosus cells, rheumatoid factor (normal value RAD are individuals with systemic lupus erythematosus < 20 IU/ml), antinuclear antibodies by immunofluores- commentary (SLE) [4–7], lupus anticoagulant and antiphospholipid cence test (rat kidney substrate), anti-DNA (radioim- syndrome associated [8], scleroderma [9–12], rheumatoid munoassay), and Ro, La, Sm, and Scl-70 by arthritis (RA) [13], ankylosing spondylitis (AS) [14–16], nephelometry to disclose autoimmune phenomena and polymyositis [17], while Turner’s syndrome has been and/or inflammatory serum subclinical abnormalities. The associated with autoimmune thyroiditis [3], juvenile histocompatibility antigen B27 (B27) was determined by rheumatoid arthritis (JRA) [18], and juvenile-onset inflam- Terasaki’s joint-to-thyroid function test (Cis bio international matory bowel disease [19]. Only one of these reports Groupe ORIS Cedex-France) using radioimmunoassay. included eunuchoid males and female subjects with an Serum levels of testosterone (double-antibody radio- β abnormal X karyotype [2]. immunoassay technique), estradiol-17 (E2) (Interna- tional CIS Sorin, Paris, France; double-antibody Our goal in the present work was to determine whether radioimmunoassay kit), follicle-stimulating hormone, male patients with untreated hypogonadism have an luteinizing hormone, and prolactin (Diagnostic Products increased risk of developing RAD, and, if so, whether Co, Los Angeles, CA, USA; double-antibody radio- there is a relation to the type of hypogonadism. immunoassay kit) (in duplicate) were determined in review patients and controls. Coefficients of intra-assay and Methods interassay variations were, respectively, as follows: The clinical criteria of male hypogonadism refers to failure testosterone, 6.0 and 10.4%; E2, 5.0 and 8.5%; follicle- of testicular function resulting in decreased production or stimulating hormone, 3.1 and 7.7%; luteinizing hormone, absence of male sex hormones and impaired spermatogen- 7.0 and 7.9%; and prolactin, 4.4 and 8.6%. X-rays were esis, whether this failure is secondary to hypothalamic and made of the lumbosacral spine, sacroiliac joints, and pituitary dysfunction or is primary testicular failure [20]. affected peripheral joints and were interpreted blind. Affected tissues were biopsied as appropriate for the From 60 patients who fulfilled the previous hypogonadism clinical signs. criteria who were seen at the outpatient Andrology Clinic, Mexico City, Mexico, from July 1998 to May 2000, 13 who Fisher’s exact test and the Mann–Whitney U test were were not receiving hormone substitution were selected for used for statistical analysis (computer package Epi-Info, this study. Version 6.00; Centers for Disease Control and Prevention, USA, World Health Organization, Geneva, Switzerland). reports The clinical criteria of male ‘hypogonadism’ refers to failure The significance limit was set at P < 0.05. of testicular function resulting in decreased production or absence of male sex hormones and impaired spermatogen- Results esis, whether this failure is secondary to hypothalamic and Age and body mass index were similar in patients and pituitary dysfunction or is primary testicular failure [20]. controls (mean ± standard deviation): respectively, age 25.3 ± 8.4 years vs 29.5 ± 7.6 years and body mass index Ten normogonadic healthy male hospital staff with similar 23.1 ± 3.3 kg/m2 vs 24.2 ± 3.6 kg/m2 (P = NS). The age and body mass index [21] constituted the control testicular volume was 4.4 ± 4.3 ml in patients and group for testicular size and hormone levels. 43.5 ± 3.5 ml in controls (P = 0.001). Nine of the 13 patients had hypergonadotropic hypergonadism, five of All the patients gave their informed consent. They and the whom had Klinefelter’s syndrome (47,XXY). The other four control subjects were given a neuroendocrine, genetic, of the 13 patients had hypogonadotropic hypogonadism and clinic evaluation, including a physical exam, in addition (46,XY); two of this group had Kallmann’s syndrome and research article to computed tomography of the sella turcica and karyotyp- two had idiopathic cryptorchidism. ing of peripheral leukocytes. The presence of secondary sexual characteristics and testicular volume (normal value Eight out of the 13 male hypogonadic patients also had > 20 ml) were noted. RAD independently of the cause of their hypogonadism. Of these, four had B27 + AS, two had SLE (in one case asso- In the patients, the rheumatolgic evaluation included a ciated with anti-phospholipid antibodies), one had JRA, and search for the presence of diagnostic criteria for SLE, one had juvenile dermatomyositis (Tables 1 and 2). We did RA, AS, psoriatic arthritis, JRA, polymyositis/dermato- not find adult RA, scleroderma, scleroderma/CREST, psori- myositis, scleroderma/CREST (calcinosis, Raynaud’s atic arthritis, or Behçet’s syndrome. Arthritis Research Vol 3 No 6 Jiménez-Balderas et al Table 1 Clinical, laboratory, and radiologic data for subgroup
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