Tissue Antigens (1982) 20, 270-273

Male infertility due to idiopathic disorders of spermatogenesis: no association with HLA G. MUELLER-ECKHARDT’, W. KRAUSE~, G. SCHIERKE’ and C. MUELLER-ECKHARDT’

‘Institute of Clinical Immunology and Blood Transfusion, and ZDepartment of Andrology and Venerology, University of Giessen, Giessen, FRG

HLA-ABC and DR antigens were determined in 65 male patients suffering from infertility due to idiopathic disorders of spermatogenesis, and in one family includ- ing 3 brothers with azoospermia. No statistically significant deviations of antigen frequencies were observed in the patient group when compared with 929 (ABC) or 206 (DR) healthy control indi- viduals. From the family data, a segregation of an hypothetical disease susceptibility gene with HLA could not be deduced. Received for publication 13 April, revised, accepted 17 May 1982

As in other “idiopathic” diseases of infectious and/or autoimmune etiology, immunogenetic factors have been suspected to play a role in male infertility due to unexplained germ cell aplasia (Ivanyi e t al. 1970). Associations with HLA have been investigated by Ivanyi et al. (1970), who found no definite relation be- tween the HLA-A/B haplotypes of 6 patients with azoospermia and their brothers with the same disorder, while Bisson et al. (1976) re- ported a higher frequency of HLA-A28 and B40 in 39 patients and Kamidono et al. (1980) of Bw35 in a group of 50 Japanese patients with idiopathic azoospermia and germ cell aplasia. No data of HLA-DR an- tigens, which presumably are of greater im- portance for disease susceptibility (Ryder e t

Supported by the Deutsche Forschungsgemein- schaft. This work is part of the thesis (M.D.) of G. Schierke.

al. 1979, Svejgaard 1979, Svejgaard et al. 1979), have as yet been published.

Because of these controversial and incom- plete results, we have evaluated a larger group of male patients with infertility due to idiopathic disorders of spermatogenesis for disease associations with HLA-ABC and D R determinants.

Patients and methods

Sixty-five unrelated male patients with fer- tility disorders ranging in age from 20 to 46 years, and one family with 3 infertile brothers were investigated. 17 patients had an azoo- spermia, 25 cryptozoospermia (< 2 x lo6 spermatozoa/ml) and 23 severe oligozoo- spermia (< 5 x lo6 spermatozoa/ml). In all cases the cause of the disturbances of sper-

0001-2815/82/090270-04 $02.50/0 @ 1982 Munksgaard, Copenhagen

HLA AND IDIOPATHIC MALE INFERTILITY 27 1

Table I . HLA-ABC and DR antigen frequencies in patients (n = 65) and controls (ABC: n = 929; DR: n = 206).

H L A P a t i e n t s Controls X 2

A 1 2 3 9

10 1 1 2 8 2 9

w30/w31 w32 w33

6 5 7 8

1 2 1 3 1 4 1 5

w16 17 1 8

w z 1 w22

27 w35

3 7 4 0

w4 1 w53

c w l w2 w3 W4 w5 w6

38.5 50 .8 29 .2 30.8

7.7 6 .2 9.2 1.5 6 .2 7.7 3.1

15 .4 20 .0 21 .5 2 6 . 2

4 .6 6 .2

26 .2 7.7 4.6

1 2 . 3 3.1 1.5 9.2

16 .9 6 .2 6 . 1 0 .0 0 . 0

4.6 10.8 30 .8 13 .8 1 0 . 8 1 6 . 9

2 7 . 6 5 2 . 3 2 5 . 8 22 .1 1 2 . 2 1 0 . 4

8 . 0 5 .5 8 . 1 6 .1 1 . 8

1 2 . 6 2 5 . 5 1 9 . 1 2 4 . 9

5 . 5 4 .5

1 6 . 3 5.9 9 . 5 9 . 8 4.0 5 . 5 8 . 5

15 .7 2 . 5

1 1 . 8 1 . 8 1.1

3 . 5 6 0 .06 0 .36 2 .63 1 . 1 6 1 . 17 0 . 1 3 1 . 9 1 0 .31 0 . 2 5 0 . 5 0

0 .42 0 . 9 8 0 .24 0 . 0 5 0 .09 0 .37 4 . 2 4 * 0 .34 0 .01 0 . 4 3 0 . 2 6 1 .91 0 . 0 4 0 . 0 7 3 .11 1 . 9 3 1 .21 0 .71

5 . 2 0 . 0 4 11 .2 0 .01 26 .7 0 .51 1 9 . 9 1 .42

6 .4 2 .25 1 0 . 3 2 .75

DR 1 1 5 . 4 2 1 . 5 1 .ll 2 29 .2 3 2 . 1 0 .24 3 26 .2 2 1 . 1 0 . 8 0 4 23.0 23 .4 0 . 0 0 5 24 .6 25 .8 0 . 0 3

w6 1 8 . 4 2 5 . 8 1 .43 7 23 .0 24 .4 0 . 0 4

* p < 0.05, not significant after correction by multiplying by the number of antigens tested (ABC antigens: n = 35).

272

K.P. K.N.

MUELLER-LCKHARDT E l AL.

K,K.

K. K. K.A.

a ,A2,318,C-,DR2 I

b 43 , Bw35 ,Cw4 ,DR1

a &,B18,C- ,DR2 a A2,B18,C- ,DR2 b A3,Bw35,Cw4 ,DR1 n. t. c A28,B14,C-,DR5 d A ~ , B w ~ ~ , C - , D R I c A28,B14,C-,DR5 Figure 1. Pedigree of family K. including three brothers with idiopathic azoospermia. (n.t. = not tested)

matogenesis was obscure. Known etiologic factors, i.e. cryptorchidism, orchitis, var- icocele, drugs, radiation, intoxication, were excluded. In addition, plasma levels of the hormones FSH, LH, and testosterone includ- ing an LH-RH test were measured in all cases. In patients with azoospermia elevated gona- dotropin levels were considered t o indicate aspermatogenesis (Franchimont et al. 1972). If gonadotropin levels were normal, the sper- matogenic arrest was confirmed or the ob- struction of efferent ducts was excluded by testicular biopsy.

H L A typing was done from heparinized peripheral blood by the standard lym- phocytotoxicity test (NIH; Terasaki & McClelland 1964). For D R typing B lympho- cytes were separated by nylon wool column (Lowry et al. 1979) and tested with prolonged incubation time (60/120 min). The antigen frequencies of patients were compared to those of 929 (ABC) or 206 (DR) unrelated healthy blood donors (controls) by x2 evalua- tion.

Results and discussion

As shown in Table 1, no statistically signifi- cant deviations of HLA-ABC frequencies were observed between patients and controls. In particular, we did not find an increased fre- quency of A28 and B40 (Bisson et al. 1976) or of Bw35 (Kamidono et al. 1980). Neither were there significant differences of DR an- tigen frequencies between both groups.

Figure 1 depicts the pedigree of a family with 3 infertile brothers due to azoospermia. None of the 4 parental haplotypes was shared by all of them, which makes the segregation of a hypothetical disease susceptibility gene with H L A unlikely.

We conclude that a significant relation be- tween HLA-A,B,C,DR antigens and male infertility due to idiopathic disorders of sper- matogenesis does not seem to exist.

It must be kept in mind, however, that our understanding of the pathogenesis of this syn- drome is still incomplete and does not permit

HLA AND IDIOPATHIC MALE INFERTILITY 273

further subdivision so far. If this eventually should become possible, an association be- tween HLA and one OT the other of the hypothetical subgroups is still conceivable.

Acknowledgment

We thank Mrs. I. Lenssen for expert sec- retarial assistance.

References

Bisson, J. P., David, G., Kolevski, P., Hors, J. & Dausset, J . (1976) Azoospermy and HLA an- tigens (abstract). In HLA and Disease, eds. Dausset, J. & Svejgaard, A., Inserm, Paris.

Franchimont, P., Millet, D., Vendrely, E., Letawe, J., Legros, J. J. & Netter, A. (1972) Relationship between spermatogenesis and serum gonadotro- pin levels in azoospermia and oligospermia. J Clin Endocrin Metab 34, 1003-1008.

Ivanyi, P., Raboch, J. & Vybiralova, H. (1970) HL-A Antigene bei Patienten mit Sper- miogenese-Stop und ihren Briidern. Andrologie 2,9-11.

Kamidono, S., Matsumoto, O., Ishigami, J., Nakao, Y. & Tsuji, K. (1980) Infertility and HLA an- tigen - Male infertility and infertile couples. - Andrologia 12, 3 17-322.

Lowry, R., Goguen, J., Carpenter, C. B., Strom, T. B. & Garovoy, M. R. (1970) Improved B cell typing for HLA-DR using nylon wool column enriched B lymphocyte preparations. Tissue An- tigens 14, 325-330.

Ryder, L. P., Andersen, E. & Svejgaard, A. (1979) HLA and Diseuse Registry. 3rd report. Munksgaard, Copenhagen.

Svejgaard, A. (1979) HLA and autoimmune dis- eases. Allergy 34, 275-281.

Svejgaard, A,, Hauge, M., Jersild, C., Platz, P., Ryder, L. P., Staub Nielsen, L. & Thomsen, M. (1979) The HLA System. 2nd ed. S. Karger, Basel.

Terasaki, P. J. & McClelland, J. D. (1964) Mic- rodroplet assay of human serum cytotoxins. Na- ture 204, 098-1000.

Address: Gertrud Mueller-Eckhardt, M. D. Institute of Clinical Immunology and Blood Transfusion University of Giessen Langhansstrasse 7 D-6300 Giessen, FRG