Gonadal Function in Male Adolescents and Young Males with Juvenile Onset Systemic Lupus Erythematosus CLOVIS A.A. SILVA, JORGE HALLAK, FABIO F. PASQUALOTTO, MÁRIO F. BARBA, MARIA I. SAITO, and MARIA H.B. KISS

ABSTRACT. Objective. To evaluate gonadal function in male adolescents and young men with juvenile onset sys- temic lupus erythematosus (SLE). Methods. Four young men with SLE underwent clinical and laboratory evaluation, testicular ultrasound, follicle stimulating , luteinizing hormone, prolactin, testosterone, and anti- antibody determination. The semen analyses were performed according to the WHO guidelines and Kruger strict criteria. All patients were asked to provide 3 semen samples over a period of 2 months. A new sample was collected 6 months later. Results. The median disease duration was 6.6 years. The median age at initial was 13.5 years. All 4 patients had severe disease with renal involvement (WHO class IV or V). The SLICC/ACR damage index at the time of study entry ranged between 0 and 3. The patients’ Tanner stage was P5G5; all reported normal and libido. Gonadal evaluation by thorough examination of the genitalia and ultrasound was normal. Anti-sperm antibodies were negative in all patients. Only one patient showed high FSH and LH levels. The initial and final semen evaluations of the 4 patients were abnor- mal (, oligoastenoteratospermia, or teratospermia). One patient was receiving azathioprine and 2 were receiving cyclophosphamide at the time of study entry. Conclusion. Although these patients had normal sexual activity and normal external genitalia, their fer- tility was decreased based on the sperm abnormalities. Serial semen analyses in larger study populations will be necessary to clarify the degree and duration of sperm abnormalities in male patients with SLE in general. (J Rheumatol 2002;29:2000–5)

Key Indexing Terms: LUPUS MALE GONADAL SEMEN HORMONE ADOLESCENT

Systemic lupus erythematosus (SLE) is a multisystem refinements in quality of life among the survivors. Despite the autoimmune disease of unknown etiology and is more preva- number of adolescents and young adults with SLE, few stud- lent in women than in men (F:M = 5:1)1. The annual incidence ies have reported the gonadal function of these patients. of juvenile onset SLE in childhood is roughly 0.4 per 100,000. or azoospermia in patients with SLE may The prognosis for children and adolescents with SLE con- have several causes including , the disease itself, tinues to improve as better access to medical care and diag- drugs used to treat the illness, disease of the genital system5,6, nostic testing have provided better detection of children with hypothalamic-pituitary-axis dysfunction7,8, autoimmunity, SLE2. With antiinflammatory therapy as well as sophisticated activity of the disease9, and especially the drugs used as pediatric care, 10-year survival rates are now found in over immunosuppressors, particularly cyclophosphamide10-15 and 80% of patients with SLE3,4. However, clinical attention has chlorambucil12-15. begun to shift away from the problems of cure and toward We studied gonadal function in 4 male adolescents and young men with SLE.

From the Pediatric Rheumatology Unit, Department of Pediatrics, Children’s Institute, and the Division of Urology Clinic, University of São MATERIALS AND METHODS Paulo, São Paulo, Brazil. Patients. Four male patients who fulfilled 4 or more 1982 American College of Rheumatology (ACR) classification criteria for SLE16, followed at the C.A.A. Silva, MD, PhD, Head, Pediatric Rheumatology Unit, Department of Pediatrics; J. Hallak, MD, PhD, Attending Physician, Division of Pediatric Rheumatology Unit of the Children’s Institute of our university hos- Urology Clinic; F.F. Pasqualotto, MD, Postgraduate student, Division of pital, were studied. Informed consent was obtained from all participants. Urology Clinic; M.F. Barba, MD, PhD, Attending Physician, Department Their actual ages ranged from 16 years and 9 months to 22 years and 10 of Pediatric Radiology; M.I. Saito, MD, PhD, Head, Adolescent Unit; months. M.H.B. Kiss, MD, PhD, Associate Professor of Pediatrics. Clinical evaluation. SLE disease activity and cumulative damage at the time Address reprint requests to Dr. C.A.A. Silva, Rua Raul Pompéia, of study entry were measured in all patients, using the SLE Disease Activity 303/43-Pompéia, São Paulo SP, Brazil CEP 05025-010. Index (SLEDAI)17 and the Systemic Lupus International Collaborating E-mail: [email protected] Clinics/ACR (SLICC/ACR) Damage Index18. SLE activity was classified into Submitted October 17, 2001; revision accepted March 7, 2002. 3 patterns: relapsing-remitting (RR), chronic active (CA), and long quiescent

Personal non-commercial use only. The Journal of Rheumatology Copyright © 2002. All rights reserved. 2000 The Journal of Rheumatology 2002; 29:9 Downloaded on September 26, 2021 from www.jrheum.org (LQ)19. Renal biopsy was classified according to the World Health Ana, CA, USA). The direct immunobead binding test detects antibodies that Organization (WHO) criteria20. The time of utilization (pre or postpubertal bind to the sperm cell surface and may impair . Antibodies attached to period) and the total dose of drug therapy [prednisone, cyclophosphamide, the sperm head are suspected to interfere with penetration, whereas methotrexate (MTX), and azathioprine (AZA)] were also determined. tail-bound antibodies may impair sperm motion. Patients were evaluated according to a questionnaire that included the age at the time they started to ejaculate (spermarche), the age of first sexual rela- RESULTS tions, and the characteristics of , libido, erection, ejaculation and The principal clinical, therapeutic, and laboratory data . We performed a thorough examination of the genitalia to assess the fertility, which included evaluation of , , vas deferens, observed in 4 male patients with SLE appear in Table 1. The scrotum, and penis. All patients were P5 and G5, compatible with adults, median and range of values of 3 initial semen analyses and based on secondary sexual characteristics according to Marshall and Tanner’s initial hormone determinations are presented in Table 2. pattern criteria of pubertal changes21. Each patient was examined by a urolo- All patients reported having normal erection, ejaculation, gist and had testicular volumes measured with the Prader orchidometer. The orgasm, and libido. There was no history of cryptorquidia, Prader orchidometer consists of 12 ellipsoid models graded from 1 to 25 ml (1 to 6, 8, 10, 12, 15, 20, and 25 ml) against which the testes were compared22. hydrocele, hypospadia, varicocele, testicular infection like The normal testicular volume value in Brazilian postpubertal adolescents mumps, cancer, tumor, orquitis, or previous testicular surgery ranges between 12 and 25 ml23. in any patient. Each patient had inadequate gonadal function Ultrasonography. Ultrasound studies were performed by experienced sonog- according to the WHO23 and Kruger strict criteria24. raphers using a 7.5 MHz sector scanner (Siemens Sonoline SL2, Erlangen, Patient 1 developed spermarche by masturbation at age 14, Germany). Testes were scanned in axial and longitudinal planes, and at least before being diagnosed with SLE, and he was sexually active 2 measurements of length, width, and thickness were obtained. The largest measurement in each dimension was recorded and used to calculate testicular at time of study entry, with his first sexual relations occurring volume using the formula for an ellipsoid, length × width × thickness × 0.52. at the age of 16. Testicular volume by Prader orchidometer The mean value in older adolescents is 15 ± 8 ml24. was normal: 20 ml in both testicles. Testicular ultrasound was Semen analyses. was performed according to the WHO crite- normal: the volume was 8.5 ml in the right testis and 10.8 ml ria25. All patients were asked to provide 3 semen samples following mastur- in the left. Anti-sperm antibody titers were absent, and high bation after 48 to 72 h of sexual abstinence over a period of 2 months and an levels of FSH (19.9 IU/l) and LH (11.0 IU/l) were observed at additional sample was evaluated 6 months later. Semen specimens were liq- uefied at 37°C for 30 min and analyzed according to volume, concentration, time of study entry. These abnormal results were repeated and total number, motility, linear velocity, linearity, lateral head displacement, and confirmed 6 months later: FSH 21.1 IU/l and LH 13.0 IU/l. sperm morphology. Five microliters of the specimens were loaded on a 20 µl SLE activity was classified as RR, the SLEDAI score was 16, Microcell counting chamber (Conception Technologies, San Diego, CA, and the SLICC/ACR Damage Index was 3 at the time of study USA). The specimens were analyzed by manual hand count as well as by a entry. He received prednisone, MTX, and AZA before study computer assisted semen analyzer (Cell Trak Semen Analyzer, CTS Version 4.0, Motion Analysis Corporation, Palo Alto, CA, USA), under 400× magni- entry. At time of study entry, he was receiving 5 mg/day pred- fication. Each slide was scanned to estimate the number of spermatozoa per nisone and maintenance phase therapy with intravenous field equivalent to 1 nl, to obtain a rough sperm concentration in million/ml. cyclophosphamide. He received a cumulative dose of This estimate was used to determine dilution criteria as follows: < 15 sper- matozoa, dilution 1:5; 15–40 spermatozoa, dilution 1:10; 40–200 spermato- Table 1. The principal clinical, therapeutic, and laboratory data for 4 male zoa, dilution 1:20; and > 200 spermatozoa, dilution 1:5. The sperm motility patients with SLE. was determined by analysis of at least 5 microscopic fields in a systematic way to classify 200 spermatozoa. The motility of each was Patient graded “a” (rapid progressive motility) and “b” (slow or sluggish progressive Variables 1 2 3 4 motility). Sperm morphology was considered normal if the sperm head, neck, midpiece, and tail were normal. Age at disease onset, yrs 14 9 10 13 Sperm concentration and motility were assessed by the WHO criteria25. Disease duration at study Sperm morphology was assessed by WHO25 and Kruger strict criteria26. entry, yrs 8 8 7 3 Oligospermia was defined as a sperm concentration < 20 million/ml. SLE clinical Astenospermia was defined as a normal sperm motility (“a” + “b”) < 50%. manifestation* A, N, S A, C, N, S, SE A, C, N, S A, N, S, SE Teratospermia was defined as a normal sperm morphology < 30%, oligoast- Renal biopsy** V IV IV V enoteratospermia as alteration of all 3 variables, and normospermia as normal (WHO criteria) results for all 3 variables. A patient was considered azoospermic when no SLEDAI at study entry 16 10 0 0 spermatozoon was seen25. Sperm morphology was also determined by Kruger SLICC/ACR Damage index strict criteria and normal sperm morphology < 14% was considered the cut- at study entry 3 1 1 0 off for an abnormal value26. Dose at study entry, g Determination of hormonal serum levels. The hormonal studies were per- Prednisone 45.4 60.5 40.33 28.4 formed at the time of study entry. The abnormal results were repeated for con- IVCF 8.0 24.6 11.1 0 firmation. Follicle stimulating hormone (FSH), luteinizing hormone (LH), MTX 5.13 0.52 5.6 0 prolactin, and testosterone were determined by fluoroimmunoassay using kits AZA 77.6 14.5 73.6 85 from Delphia® for time resolved fluoroimmunoassay (Wallac Oy, Turku, Finland). * A: arthritis; C: central nervous system disease; N: nephritis; SE: serositis; Detection of anti-sperm antibodies. Anti-sperm antibodies were measured at S: skin abnormalities. ** IV: diffuse proliferative glomerulonephritis; V: study entry and were determined by direct immunobead test using kits from membranous glomerulonephritis. IVCF: intravenous cyclophosphamide; Immunobead® rabbit anti-human Ig (H + l0) reagent (Irvine Scientific, Santa MTX: methotrexate; AZA: azathioprine.

Personal non-commercial use only. The Journal of Rheumatology Copyright © 2002. All rights reserved. Silva, et al: Gonadal function in SLE 2001 Downloaded on September 26, 2021 from www.jrheum.org Table 2. Median and range of values of 3 initial semen analyses and initial hormone determinations in 4 male patients with SLE.

Normal Patient Limits 1 2 3 4

Semen variables Volume, ml 2–5 3.5 1.0 2.0 2.4 (3.0–4.5) (0.8–1.5) (1.3–2.2) (1.0–2.5) Viscosity, min < 30 10 10 10 7 (7–10) (6–12) (7–12) (6–10) Sperm concentration, × 106/ml > 20 0 0.3 69 54 (0.2–0.4) (61–92) (46–131) Total sperm number × 106/ejaculate > 40 0 0.3 136 131 (0.3) (120–138) (112–135) Sperm motility (“a” + “b”) (%) > 50 0 10 50 71.8 (0–50) (50–79) (64–78) Linear velocity, µm/s > 15 0 0 48 37.6 (37–48) (32.3–42) Linearity, % > 19 0 0 77 60 (63–77) (60–68) Lateral head displacement, µm/s > 2.0 0 0 2.1 2.5 (2.1–2.4) (2.1–2.7) WHO normal morphology, % > 30 0 0 16 15 (8–17) (12–16) Kruger normal morphology, % > 14 0 0 3 2 (1–3) (2–3) FSH, IU/ml 1–12 19.9 11.1 11.7 6.5 LH, IU/ml 1.4–9.2 11.0 9.0 6.6 5.3 Prolactin, ng/ml 2.3–11.5 7.1 4.7 5.2 31 Testosterone, ng/ml 200–950 479 904 501 571

cyclophosphamide of 140 mg/kg. The 3 initial semen analyses after the diagnosis of SLE. He was sexually inactive at time of were similar and termed azoospermic. The final semen sam- study entry. Testicular volume by Prader orchidometer was ple, evaluated 6 months after the initial one, showed mainte- normal: 25 ml in the right testis and 20 ml in the left. nance of azoospermia. At that time, he had a SLEDAI score of Testicular ultrasound was normal: the volume was 9.1 ml in 4 and had not been receiving cyclophosphamide for 3 months. the right testis and 8.9 ml in the left. Anti-sperm antibody Patient 2 developed spermarche by masturbation at age 14, titers were absent and serum hormone levels were normal at after the diagnosis of SLE. He was sexually active at time of time of study entry. Initial SLE activity was classified as LQ, study entry, with his first sexual relations occurring at age 16. the SLEDAI score was 0, and the SLICC/ACR Damage Index Testicular volume by Prader orchidometer was normal: 20 ml was 1. Prior to the study, he had received prednisone, MTX, in the right testis and 25 ml in the left. Testicular ultrasound AZA, and intravenous cyclophosphamide. At study entry, he was normal: the volume was 9.0 ml in right testis and 9.5 ml was only receiving 10 mg/day prednisone. He received a in left. Anti-sperm antibody titers were absent and serum hor- cumulative dose of cyclophosphamide of 185 mg/kg in the mone levels were normal at time of study entry. Initial SLE prepubertal period, 6.5 years before the initiation of the study. activity was classified as RR, the SLEDAI score was 10, and The 3 initial semen analyses were similar and were termed ter- the SLICC/ACR Damage Index was 1. He had received pred- atospermic. The final semen sample, evaluated 6 months after nisone, MTX, and AZA before study entry. At study entry he the initial one, showed maintenance of teratospermia. At that was receiving 10 mg/day prednisone and maintenance phase time he had a SLEDAI score of 0 and was receiving 10 therapy with intravenous cyclophosphamide. He received a mg/day prednisone. cumulative dose of 396 mg/kg cyclophosphamide. The 3 ini- Patient 4 developed spermarche by masturbation at age tial semen analyses were similar and termed oligoastenoter- 12.9, before the diagnosis of SLE. He was sexually inactive at atospermic. The final semen sample, evaluated 6 months after time of study entry. Testicular volume by Prader orchidometer the initial one, showed only teratospermia. At that time he had was normal: 20 ml in the right testis and 20 ml in the left. a SLEDAI score of 4 and had not been receiving cyclophos- Testicular ultrasound was normal: the volume was 11.0 ml in phamide for 5 months. the right testis and 10.0 ml in the left. Anti-sperm antibody Patient 3 developed spermarche by masturbation at age 13, titers were absent and serum hormone levels were normal at

Personal non-commercial use only. The Journal of Rheumatology Copyright © 2002. All rights reserved. 2002 The Journal of Rheumatology 2002; 29:9 Downloaded on September 26, 2021 from www.jrheum.org time of study entry. Initial SLE activity was classified as LQ, Traditionally, an initial diagnosis of infertility depends on the SLEDAI score was 0, and the SLICC/ACR Damage Index sperm concentration, motility, and morphology25,35. All of our was 0. He was receiving 10 mg/day prednisone and 100 patients had abnormal semen analysis and would be diag- mg/day AZA at study entry and has not received any other nosed with infertility. According to the WHO definition for immunosuppressive agents. The 3 initial semen analyses were semen analysis25, in the initial evaluation one patient was con- similar and were termed teratospermic. The final semen sam- sidered azoospermic, one oligoastenoteratospermic, and 2 ter- ple, evaluated 6 months after the initial one, showed mainte- atospermic. Despite a normal sperm concentration, patients nance of teratospermia. At that time he had a SLEDAI score with teratospermia have difficulties in establishing a pregnan- of 0, and was receiving 10 mg/day prednisone and 100 cy. Kruger, et al found that patients with less than 4% of nor- mg/day AZA. mal spermatozoa have a low rate26. The gonadal function of these patients may be changed DISCUSSION according to the activity and the severity of the disease, The improved prognosis for juvenile SLE has resulted in autoimmunity due to sperm antibodies, and drugs used. patients reaching their reproductive years and wishing to start Because the is involved in , it is there- a family. SLE is a serious disease characterized by remissions fore very susceptible to damage14. and exacerbations of the multiple clinical manifestations, with decreased libido, erectile dysfunc- requiring aggressive treatment, which can cause permanent tion, and failure to ejaculate have been reported in 19 to 35% damage to the gonadal tissue. of men with SLE36. The 4 patients we describe had a severe The age at the time of the first ejaculation in our patients disease, requiring immunosuppressive treatment. Two were ranged between 13 and 14 years, comparable with data from undergoing an SLE flare requiring cyclophosphamide therapy normal adolescents. As in women, in whom the at the time of the study, but this clinical condition did not does not mean complete reproductive functionality, the full interfere with their sexual activities. reproductive capacity in men is achieved 21 months after the Reichlin, et al9 have found IgG anti-sperm antibodies in 10 first ejaculation phenomenon5,27-29. of 24 patients with SLE. The presence of the antibody corre- Testicular volume assessment is of utmost importance lated with anti-DNA titers and increased disease activity. The when we evaluate gonadal function because seminiferous detection of sperm antibodies by electronic microscopy tubules represent 95% of the testis volume. Usually, there is implied a disturbance in the acrosome of the spermatozoa. In symmetry between the 2 testicles, except in cases of varico- our study, none of the 4 patients had anti-sperm antibodies cele and cryptorchidism. It is very important to perform a tes- determined by direct immunobead test. This methodology is ticular ultrasound to rule out varicocele even when the testic- different from the one used by Reichlin, et al9, because it ular volume is normal6,30. In our study, testicular volume was detects not only antibodies to the acrosome but also to other considered normal, independent of the method used to evalu- parts of the spermatozoa such as the head, midpiece, and tail. ate it. To our knowledge, this is the first study to evaluate Immunosuppressive therapy used in patients with can- gonadal function (semen analysis and hormones) in young cer14,15,37 and nephrotic syndrome13, may reduce the germinal men with SLE. epithelium, lowering the production of spermatozoa depend- Three patients had normal hormone levels and only the ing upon the age at treatment initiation, the cumulative dose patient with azoospermia presented with a higher FSH level of therapy, and the timing of drug administration (pre or post- and a slight elevation in the LH level, with normal testos- pubertal). AZA has no obvious effect on fertility. However, terone and prolactin levels. As expected, testosterone levels MTX may produce abnormalities in spermatogenesis, which were normal, even in the patient with azoospermia. In agree- are temporary and reversible when the drug is withdrawn12. ment with other studies15,31, secondary sexual characteristics Further, low impregnation rate due to low sperm count, were normal. altered motility, or abnormal morphology is frequently seen FSH is the major marker of seminiferous epithelia function with cyclophosphamide10-15 and chlorambucil treatment12-15. and levels twice as high as normal values suggest definitive Usually, spermatogenesis is suppressed for 1 to 3 weeks with testicular damage32. A peptide made by Sertoli cells, inhibin the use of cyclophosphamide, resulting in abnormal semen B, seems to be primarily involved in the negative feedback analysis10. Patient 2 was diagnosed as oligoastenoteratosper- regulation of FSH secretion33. The discordance between nor- mic in the initial evaluation while receiving cyclophos- mal LH and high FSH could be explained by inhibin B defi- phamide; the final semen analysis performed 5 months after ciency due to Sertoli cell dysfunction in patients with SLE8. cyclophosphamide discontinuation revealed only teratosper- Hypoandrogenism is present in some patients with SLE mia. and may be relevant in the disease pathogenesis8. Male adults Although the gonadotoxic effect of immunosuppressive and postpubertal adolescents with SLE may present signifi- agents depends on their mechanisms of action, dose, and num- cantly higher levels of FSH and LH7,34 and low testosterone ber of cycles, it is not possible to predict which patients will levels34. become sterile and which will recover testicular function after

Personal non-commercial use only. The Journal of Rheumatology Copyright © 2002. All rights reserved. Silva, et al: Gonadal function in SLE 2003 Downloaded on September 26, 2021 from www.jrheum.org treatment13,15. Regarding this particular concern, the pubertal ACKNOWLEDGMENT gonad appears at risk, although postpubertal adolescents are We thank Drs. Eloisa Bonfá, Vera H.K. Koch, Sami Arap, Bernadete L. more vulnerable to permanent sterility14,37. A metaanalysis Liphaus, Lucia M.M.A. Campos, and Marta B. Leal for advice and Christiany Locambo for performing the semen analyses. was performed by Latta, et al13 regarding the use of cytotoxic treatment for frequently relapsing nephrotic syndrome in chil- REFERENCES dren. The authors showed that there is no safe threshold for a 1. 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