THE RESULTS OF INTERMITTENT HIGH DOSE STEROID THERAPY FOR MALE INFERTILITY DUE TO ANTISPERM ANTIBODIES*

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1 FERTILITY AND STERILITY Copyright C> 1981 The American Fertility Society Vol. 36, No.3, September 1981 Printed in U.SA. THE RESULTS OF INTERMITTENT HIGH DOSE STEROID THERAPY FOR MALE INFERTILITY DUE TO ANTISPERM ANTIBODIES* WILLIAM FORBES HENDRY, CH.M., F.RC.S.tll JITKA STEDRONSKA, S.M.L.S.O.:!: JAROSLAVA PARSLOW, RN.D.R LOUIS HUGHES, M.B., D.RC.O.G.II Fertility Clinic and Seminology Laboratory, Chelsea Hospital for Women, London, England, and Williamson Laboratory and Department of Urology, St. Bartholomew's Hospital, London, England Forty-five males who had been infertile for 2 to 10 (average 5.3) years, with significantly positive antisperm antibody tests (serum spermagglutination titers more than 32) and demonstrably impaired sperm penetration of cervical mucus, were treated with repeated 7-day courses of methylprednisolone (MP) 32 mg three times a day from days 21 to 28 (in a few cases days 1 to 7) of their wives' menstrual cycles. Antisperm antibody tests were repeated after treatment and related to the occurrence of pregnancy in the wife. Fourteen wives (31%) became pregnant in a cycle following treatment of the husband. The production of pregnancy was always associated with a marked drop in sperm immobilizing titer and usually with disappearance of antibodies from seminal plasma; both of these effects were sometimes observed without a significant change in serum spermagglutination titers. Three patients (6%) had transient severe side effects, and 14 (26%) have had mild side effects, out of 54 patients treated so far. Fertil Steril36:351, 1981 Antisperm antibodies can be detected in the sera of 8% to 13% of naturally infertile males,1, 2 and the higher the titer of antibodies in the sera, the more likely they are to be present in the seminal plasma as well. 3 If there are antisperm antibodies in the seminal plasma, they can interfere with normal sperm penetration of cervical mucus; the sperm become attached to glycoprotein mi- Received February 18, 1981; revised and accepted April 3, *Supported by grants from the Joint Research Board, St. Bartholomew's Hospital, and from the Royal College ofobstetricians and Gynaecologists. tconsultant, genitourinary surgeon, St. Bartholomew's Hospital.. :!:Senior scientific officer, Seminology Laboratory, Chelsea Hospital for Women. Scientific research officer, Williamson Laboratory, St. Bartholomew's Hospital. IIClinical Assistant, Fertility Clinic, Chelsea Hospital for Women. IlReprint requests: Mr. W. F. Hendry, Chelsea Hospital for Women, Dovehouse Street, London SW3, England. 351 celles in the mucus and thus show a characteristic nonprogressive shaking movement on sperm-cervical mucus contact testing. 4-6 Antisperm antibodies may also interfere with sperm-egg fusion by blocking specific receptors on the sperm surface. 7 Certainly it has been shown that impairment of sperm penetration of cervical mucus, which is associated with antisperm antibodies, is also associated with impaired fertility.8 Since the importance of antisperm antibodies as a cause of male infertility was recognized, we have looked for them in the husbands of infertile marriages, first through serum spermagglutination tests in men who were unable to produce a satisfactory postcoital test, and more recently by the direct mixed antiglobulin reaction (MAR test),9, 10 applied as a screening test to the semen specimens of all the husbands attending the clinic. When a positive result was obtained, the finding was checked for significance by measurement of antibody in seminal plasma and by sperm-cervical mucus contact testing. Provided these tests

2 352 HENDRY ET AL. September 1981 were also positive, the patients'havebeen treated with steroids. Initially, we used prednisone 5 mg three times a day for up to 12 months; considerable improvement in low sperm counts was obtained, but only four pregnancies (14%) were produced by 29 patientsy We therefore changed to intermittent high-dose methylprednisolone (MP) (32 mg three times a day for seven days in alternate cycles from days 21 to 28 of the wife's menstrual cycle) as recommended by Shulman,12 and our initial results were encouraging (five pregnancies in nine couples treated). We have now treated 45 subfertile men by this method, and the results have been analyzed in terms ofthe changes produced in antisperm antibody levels, pregnancies occurring in the wives, and side effects noted by the patients. MATERIALS AND METHODS Forty-five men, aged between 24 and 46 years (average 31.7), were seen because of infertility lasting from 2 to 10 years (average 5.3). Forty-two men were "naturally infertile,"* of whom 5 had a past history of epididymitis, 4 testicular injury, 2 venereal disease, 1 mumps orchitis, and 2 very tight foreskins removed as adults; in all, 14 (33%) of these 42 had a history of a possible predisposing factor. In addition, two men had had reversal of vasectomy, and one had had successful epididymovasostomy. The average of at least two sperm counts on each patient prior to treatment are shown in Table 1. Antisperm antibodies were measured in serum before and after treatment by the gelatin agglutination test (GAT)13 and the sperm immobilization test (SIT)14;all patients in this study had pretreatment GAT titers of 32 or more (this has been shown to be the level above which antisperm antibodies are likely to have a significant effect on fertility15). Antibodies were also measured in - seminal plasma before and after treatment in 32 patients. Mixed antiglobulin reaction (MAR test) was done for IgG antibodies by methods described elsewhere,9, 10 and a few patients had MAR testing for IgAantibodies using red cells sensitized with anti-rh antibody ofiga type and antihuman IgA antiglobulin (this method is still under trial). Sperm-cervical mucus contact testing was done *Riimke 3 has pointed out that naturally infertile men differ from vasectomized men in that antisperm antibodies occur in seminal plasma more frequently in the former group. It is, th~refore, important to distinguish between these two populations of men. TABLE 1. Distribution of Average Sperm Counts of 45 Patients and Treatment with Methylprednisolone treatment treatment Spenn count (millions per m\) >41 Unknown by methods described elsewhere16 with the use of fertile donor. sperms and mucus wheneverpossible as a crossed hostility test. All the wives were under the care of consultant gynecologic colleagues, and tubal patency and ovulation were checked and corrected if necessary before the husbands were treated. Poor postcoital test results were observed in all couples prior to treatment, and positive sperm-cervical mucus contact test results with observation of the shaking phenomenon were confirmed in all cases in which this test was performed. giving treatment with steroids, patients were checked for a family history of diabetes, and fasting blood sugar, liver function tests and a chest roentgenogram was done. Dyspepsia was fully investigated, and appropriate treatment was given if necessary prior to and during therapy (usually with antacids and, in one case, with cimetidine). Patients were told of the risks involved and ~dvised to abstain from alcohol while on treatment. Methylprednisolone (MP), 32 mg three times a day with meals, was given to the husband for 7 days from days 21 to 28 of his wife's menstrual cycle. If no serious side effects occurred, and if the wife did not become pregnant, the treatment was repeated in alternate months for 6 months. Antisperm antibody levels in serum and seminal plasma were rechecked as often as possible after treatment. In a few cases, serial antibody estimations (every 2 or 3 days for 10 days) were made following the third course of MP to allow fine adjustment of the timing of future courses of treatment. Ten men received up to three additional monthly courses of MP at times ranging from days 1 to 8 to days 5 to 12 of successive cycles, depending on the results of these additional serial antibody tests. In two patients this was the primary treatment given. Enquiry regarding-side effects or pregnancy in the spouse was made at each visit, and no patient was lost to follow-up. The serum and seminal plasma specimens from 30 patients at one hospital (CHW), taken before and after treatment, were stored at - 20 C and retested simultaneously with the use of sperm

3 Vol. 36, No.3 STEROID THERAPY FOR MALE INFERTILITY 353.Titer ~1, o Wife Pregnant ( 14 ) ~ ~ Wife Not Pregnant (31 ), ",,, " '",. FIG. 1. Serum gelatin agglutination test titers before and after steroid therapy, comparing men whose wives did and did not:become pregnant. There is little difference between the two groups. from a single donor. These results have been used in Figures 1 and 2. At the other hospital (SBH) samples were tested at different times but always using sperm from a single donor. No patient crossed from one hospital to the other. 'RESULTS Twenty-eight patients completed three or more courses ofmp, 11 received two courses, and 6 had only one course. Fourteen wives (31%) became pregnant in the cycle following treatment of the husband: 2 after one course, 6 after the second course, and 6 after the third or subsequent courses. Eleven pregnancies occurred after treatment was given from days 21 to 28, and 3 after treatment was given to 10 men from days 1 to 7 or later. One miscarriage occurred. Sperm counts following treatment are shown in Table 1; counts of 20 million per milliliter or above were obtained by 39 (87%) of the 45 men, compared with 29 (64%) before treatment. The GAT results before and after treatment are shown in Figure 1; there is no evidence that the titers fell more profoundly in men whose wives became pregnant, compared with those who did not. The SIT titers in 33 men tested in one laboratory (CHW) before and after treatment are shown in Figure 2; production of pregnancy appeared to be associated with a fall in sperm immobilization titers to zero or near zero; however, a similar fall was obtained in many men whose wives did not become pregnant. Seminal plasma antibody testing was introduced in the latter part of this study, and it is difficult to draw firm conclusions as yet; however, serial testing showed that the steroid treatment caused the antisperm antibodies to disappear from seminal plasma in six patients, two of whose wives became pregnant (Table 2). An example of serial sperm counts, MAR test results, and antibody levels in serum and seminal plasma is shown in Table 3 in one patient who received MP from days 1 to 7 in three successive cycles. The rise in sperm counts and fall in serum GAT and SIT titers that accompanied MP therapy can be observed; the MAR test for IgA became negative as the seminal plasma antibodies disappeared; however, the MAR test for IgG stayed positive. Table 4 shows serial sperm counts and MAR test (lgg) results for a period of 3 weeks before and after the third course of MP in a man whose initial serum GAT titer was 256 and had fallen to 16 prior to this treatment. The MAR test became negative on the third posttreatment day at which time good sperm penetration cjf donor cervical mucus was observed. Titer o Wife Pregnant (10) FIG. 2. Serum sperm immobilization test titers before and after steroid therapy. Production of pregnancy appears to be associated with a fall in sperm immobilization titer to near zero.

4 354 HENDRY ET AL. September 1981 TABLE 2. Relationship Between Presence or Absence of Seminal Plasma Antibodies (by GAT Testing) and Treatment, and Occurrence of Pregnancy in the Spouse a Wife pregnant Wife not pregnant Seminal plasma antibodies present (GAT test) treatment /24 treatment /25 aseminal plasma antibody testing was introduced late in this study, and not all patients were tested. Altogether we have treated 54 patients with MP (including 9 patients described previously who had one course of MP that was not synchronized with the wife's cycle ll ). Three (6%) experienced such severe side effects that treatment was discontinued; one had marked dyspepsia, and treatment was suspended until he had had a course of cimetidine; he subsequently tolerated two further courses of MP, taking one tablet of cimetidine 1 hour before each dose of MP. One patient had a small hematemesis, and no further treatment was given. One patient developed transient pain in the hips lasting for a few days and refused further treatment. In addition, 14 (26%) other patients experienced less severe side effects: transient pain in the hips (3), dyspepsia (1), headaches (1), flashing lights (2), timitus (1), aggressive behavior usually directed against the wife (3), or marked blotchy face and acne (3). In general, men who were fit and worked in physically demanding occupations suffered fewer side effects and responded less well than men who were unfit and had sedentary occupations. DISCUSSION These results confirm that intermittent high doses of steroids are an effective treatment for infertility caused by antisperm antibodies in the male. The previous long history of infertility (average 5.3 years) and the production of pregnancies that coincided with profound drops in sperm immobilization titers and seminal plasma antibody levels, makes it reasonable for one to ascribe the pregnancies to the results of this therapy. The success rate (31%) is comparable to that (30%) described by Shulman et al. 17 and is certainly better than that obtained by long-term low doses of steroids (14%) or a single course of MP not synchronized with the wife's cycle (11%), described in our previous communication. ll It appears that successive courses of MP produce a stepwise decrease in antisperm antibody levels (Table 3), and this decrease may explain why most pregnancies occurred after the second or third courses of MP. The optimum timing of high-dose steroid therapy remains to be defined, and it may vary from patient to patient. We preferred to wait and see whether the wife was pregnant before giving another course from days 21 to 28 of the wife's cycle, and hence gave the treatment in alternate cycles. If the wife's menstrual period happened to be a few days late, the timing of the therapy in relation to subsequent ovulation went awry. Our sequential antibody studies completed so far indicate that it may be preferable to start the steroid therapy for the husband when the wife's menstrual period starts, in which case it could be given in successive months. The exact timing can be adjusted by serial observations of sperm counts, MAR tests, and antibody levels (Table 4). The present dose of steroids appears to cause side effects in some patients and to be ineffective in others. There may be a case for adjusting the dose downward for those that respond well, especially if they experience side effects, and upwards for those who do not respond, although it might be advisable to administer such massive doses under MP" MP MP TABLE 3. Serial Sperm Counts, MAR Tests, and Antisperm Antibody Titers Following Three Courses of MP Given Patient N. Y., Age 31, in Successive Months from Day 1 to Day 7 of the Wife's Menstrual Cycle Antisperm antibodies Treatment Date Sperm count MAR test Serum Seminal plasma mimi % Motility IgG IgA GAT SIT GAT SIT 30/ / /1/ /3/ /4/ /5/ amp, methylprednisolone 32 mg TDS for 7 days.

5 Vol. 36, No.3 STEROID THERAPY FOR MALE INFERTILITY 355 TABLE 4. Serial Sperm Counts and MAR Tests (lggj and a Third Course of MP, in a Patient Whose GAT Titer had Fallen from 256 to 16 Two. Previous Courses of MP Time in relation Sperm count MAR test to 7 day course of MP (IgG) mimi % Motility Day Day Day Day Day 7 Day surveillance in a hospital. Serious side effects have been few so far, but we believe that it is essential for the patient and his wife to be made fully aware of all the possible consequences ofthis form of therapy. Therapy for antisperm antibodies is demanding on the time of clinical and laboratory staff, it requires the patience and perseverance of the couple concerned, and it can produce severe side effects. It is therefore essential that one make sure before starting treatment (1) that the antisperm antibodies are significantly interfering with sperm activity by sperm-cervical mucus contact testing; (2) that the husband's sperm count is as good as possible; and (3) that the wife has patent tubes and the presence and timing of ovulation have been established. Recent evidence from vasectomy reversal patients has supported our belief that the presence or absence of antisperm antibodies in seminal plasma may be the critical factor in determining whether or not pregnancy occurs in the spouse. 18 intermittent highdose steroid therapy, we have observed, seminal plasma antibodies may appear-sometimes transiently, sometimes more permanently-even though serum antibodies persist (Tables 3 and 4). However, many of these patients' wives did not become pregnant, and on further detailed investigation, including sperm-cervical mucus contact testing, disorders of ovulation were detected in some women who had previously been declared normal. Close liaison between staff looking after the husband and the wife is clearly essential in the management of these couples. Acknowledgments. We wish to thank Militsa Philippou, Nicky Day, B.Sc., and Richard A. Lake, B.Sc., for technical assistance in the seminology laboratory at Chelsea Hospital for Women. REFERENCES 1. Halim A, Antoniou D: Autoantibodies to spermatozoa in relation to male infertility and vasectomy. Br J Urol 45:559, Hendry WF, Morgan H, Stedronska J: The clinical significance of antisperm antibodies in male subfertility. Br J Urol 49:757, Riimke P: Autoantigenicity of spermatozoa. In Spermatozoa, Antibodies and Infertility, Edited by J Cohen, WF Hendry. Oxford, Blackwell, 1978, p Kremer J, Jager S: The sperm-cervical mucus contact test: a preliminary report. Fertil Steril 27:335, Kremer J, Jager S: Characteristics of anti-spermatozoal antibodies responsible for the shaking phenomenon with special regard to immunoglobulin class and antigen-reactive sites. Int J Androl 3:143, Jager S, Kremer J, Kuiken J, van Slochteren-Draaisma T: Immunoglobulin class of antispermatozoal antibodies from infertile men and inhibition of in vitro sperm penetration into cervical mucus. Int J Androl 3:1, Tzartos SJ: Inhibition of in vitro fertilization of intact and denuded hamster eggs by univalent antisperm antibodies. J Reprod Fertil 55:447, Fjallbrant B: Interrelation between high levels of sperm antibodies, reduced penetration of cervical mucus by spermatozoa, and sterility in men. Acta Obstet Gynecol Scand 47:102, Jager S, Kremer J, van Slochteren-Draaisma T: A simple method of screening for antisperm antibodies in the human male. Int J Fertil 23:12, Hendry WF, Stedronska J: Mixed erythrocyte-spermatozoa antiglobulin reaction (MAR test) for the detection of antibodies against spermatozoa in infertile males. J Obstet Gynaecol 1:59, Hendry WF, Stedronska J, Hughes L, Cameron KM, Pugh RCB: Steroid treatment of male subfertility caused by antisperm antibodies. Lancet 2:498, Shulman S, Harlin B, Davis P, Reyniak JV: Immune infertility and new approaches to treatment. Fertil Steril 29:309, Kibrick S, Belding DL, Merrill B: Methods for the detection of antibodies against mammalian spermatozoa. II. A gelatin agglutination test. Fertil Steril 3:430, Isojima S, Li TS, Ashitaka Y: Immunologic analysis of sperm-immobilizing factor found in sera of women with unexplained sterility. Am J Obstet Gynecol101:677, Riimke P, van Amstel N, Messer EN, Bezemer PD: Prognosis of fertility of men with sperm agglutinins in the serum. Fertil Steril 25:393, Morgan H, Stedronska J, Hendry WF, Chamberlain GVP, Dewhurst CJ: Sperm/cervical mucus crossed hostility testing and antisperm antibodies in the husband. Lancet 1:1228, Shulman S, Mininberg DT, Davis JE: Significant immunologic factors in male infertility. J Urol 119:231, Linnet L, Hjort T, Fogh-Andersen P: Association between failure to impregnate after vasovasostomy and sperm agglutinins in semen. Lancet 1:117, 1981