Male Infertility: X. Medical Therapy en Idiopathic Infertile Males

Lee, Hee Yong; Kim, Ha Young

Abstract

Medical therapy was attempted on 210 idiopathic infertile males with spermatogenic disturbances During the past 7 years (1972-1978). and the clinical results obtained were summarized as follows: 1. The subjects were composed of 166 cases of oligospermias with sperm counts of less than 30* 106/ml, and motility of less than 40% and 44 cases of testicular azoospermias. Patients with small testis, with high FSH, with Sertoli cell only syndrome, and with tubular hyalinization were excluded in this study(Table 1). 2. The clinical characteristics of the subjects: An average age of the patients was 33 (22-45), and that of their sexual partners, 29 (21-38). An average duration of infertile marital life was 3 years (1-16 years). An average frequency of sexual intercourse was 3 per week (1-6/week). An average volume (size) of testis was 15ml (5-25ml). Testicular biopsies which had been performed on 44 azoospermias revealed that germinal cell arrest in 27%, peritubular fibrosis in 34%, and hypospermatogenesis in 39%. Mean value of plasma FSH was 5.2IU/L (1.O-13.0IU/L) ; LH, 4.9IU/L (0.8- 13.8IU/L) ; and testosterone, 540ng/dl (290-845ng/dl). Seminal fructose was 283mg/dl (125-405mg/ dl) (Table 1). 3. Medical therapy was continued for at least 3 months (1 treatment unit) since complete cycle from spermatogonium to mature sperm is estimated to require 70+/-4 days. An average duration of treatment was 6 months (2 units) in this series. At least 3 semen samples were analyzed before instituting regimens for standardization of baseline levels of each patient, and a similar number of ejaculates monthly during and after the therapy to ascertain the usefulness of the therapy. 4. In order to assess the efficacy of the medical therapy for faulty spermatogenesis, the following tentative criteria were used: Improved represents fertility index unit (sperm count(1000000/ml) Xsperm motility(%) / 100000000) before the treatment improved more than 10 units after the treatment. ""Unchanged"", no remarkable changes before and after the therapy. ""Deteriorated"", spermiogramme of post-treatment decreased after the therapy. Pregnancy achievement was also evaluated. 5. Treatment groups and regimens used were as follows(Table 2): 1) Oligospermia group: (1) Liothyronine group . Triiodothyronine (Thyronamine. Takeda. Japan), 25-50mcg daily by mouth, was administered to 13 cases. Improvement was found in 15%, while deterioration was noted in 23% of the 13. Pregnancy resulted in 1 case. (2) Vitamins group : Vitamedin composed of biotin, 100mg; vitamin B6, 100mg; vitamin B12, 1mg; and vitamin E, 300mg (Sankyo Zoki. Japan). 1gm/day orally. was given to 5 cases. Improvement was found in 20% of the 5.(3) L-Arginine group: L-Arginine monohydrochloride, amino acid (Rikagaku, Japan), 500mg/day. was administered by mouth to 20 cases. Improvement was noted in 30% of the 20. Pregnancy occurred in 2 cases. (4) AICAMIN group: AICAMIN, 4-amino-5-imidazole carbotamide orotate, nucleic acid precursor (Fujizawa, Japan), 600mg/dey, was given by mouth to 18 cases. Improvement was found in 33% of the 18. Pregnancy induced in 2 cases. (5) ATP group: Adenosin triphosphate (ATP, Adephos, Kowa. Japan), 300mg/day orally, was given to 6 cases. Improvement was noted in 33% of the 6. Pregnancy took place in 1 case. (6) Clomiphene group: Clomiphene citrate, l-(p-B-diethyl amino-ethoxyl phepyl) 1-2 diphenyl-2- thloroethylene (Samsung, Korea), 75mg/day, was administertd by mouth to 7 cases. Improvement was found in 29% of the 7. Pregnancy resulted in 1 case. (7) Mesterolone group: Oral androgen, Mesterolone (l a-metbyI-5 a-androstane-17B-o1-3-one) (UpJohn. Korea). 50-75mg/day orally, was given to 17 cases. Improvement was noted in 29% of the 17. Pregnancy achieved in 2 cases. (8) Testosterone rebound group: Depot testosterone cypionate (Schering, Korea), 250mg thrice a month, was administered intramuscularly to 15 cases. Improvement was shown in 27%. while deterioration was found in 33% of the 15. Pregnancy occurred in 2 cases. (9) HCG group , Human chorionic gonadotropin, (Puberogen, Sankyo Zoki, Japan; Tong-A, Korea), 3. 000IU every 5 days intramuscularly, was administered to 20 cases. Improvement was found in 31% of the 20. Pregnancy resulted in 2 cases. (10) Liothyronine + L-Arginine +AICAMIN combination group : Combined use of Liothyronine, 50mcg/day; L-Arginine, 500mg/day; and AICAMIN, 600mg/day. was given by mouth to 26 cases. Improvement was noted in 35% of the 26. Pregnancy occurred in 4 cases. (11) HCG+ Testosterone combination group : Combined use of HCG (Puberogen), 3.000IU every 5 days intramuscularly, in conjunction with Depot testosterone, 250mg monthly intramuscularly. vas administered to 9 cases. Improvement was shown in 33% of the 9. Pregnancy took place in 1 case (12) Liothyronine +L-Arginine +AICAMIN+HCG+ Testosterone combination group : Combined use of Liothyronine, 50mcg/day; L-Arginine, 500mg/day; and AICAMIN, 600mg/day; and HCG, 3,000 IU every 5 days intramuscularly, and Depot testosterone, 250mg/month intramuscularly, was administered to 14 cages. Improvement was found in 13% of the 14. Pregnancy was resulted in 3 cases. In a total of 166 oligospermias, improvement was noted in 51 cases (31%). and pregnancy occurred it 21 cases (13%), Pre-treatment sperm counts of 21X 10s/ml, and motility of 34% increased to 36X 106/ml, and 48% respectively after the treatment in 51 cases of oligospermia group. That is. fertility index increased from 7 units before treatment to 17 units after treatment(Table 3). 2) Azoospermia group : (1) Clomiphene group: Clomiphene citrate, 50-75mg/day orally. was given to 4 cases. No improvement was observed in this group. (2) HCG group: HCG (Puberogen), 3, 000IU every 5 days intramuscularly, was administered to 4 cases. No improvement was observed is this group. (3) HCG +Testosterone combination group : Combined use of HCG, 3.000IU every 5 days intramuscularly with Depot testosterone, 250mg/month intramuscularly, was administered to 8 cases. No improvement was observed in this group. (4) Liothyronine +L-Arginine + AICAMIN+HCG +Testosterone combination group : Combined use of Liothyronine, 50mcg/day; L-Arginine, 500mg/day; and AICAMIN, 600mg/day orally, and HCG, 3. 000IU, every 5 days intramuscularly; and Testosterone depot, 250mg/month intramuscularly, was administered to 28 cases. Viable sperm were produced in counts of 2-40X 106/ml in 7 cases of the 28. Pregnancy resulted in 2 cases(Table 4). 3) In summary of the medical therapy on the 210 idiopathic infertile males of faulty spermatogenesis, improvement was observed in 51 cases (28%), and pregnancy occurred in 17 cases (8%). No change was found in 123 cases (59%) and pregnancy resulted in 4 cases (2%). Deterioration was noted in 29 cases (17%), and pregnancy achieved in 2 cases (1%) in the present series. 6. For evaluation of the infertile males, complete history taking, physical examination, laboratory examination were carried out(Table 5). Testicular size should be measured on infertile patients by orchidometers. Average size of testis of the 210 patients revealed 15ml in volume, while that of normal fertile Korean male is 19+/-5ml(Table 6). Usually sperm production was almost not possible in hypogonadism whose testicular volume was less than 8ml. 7. In testicular biopsy, the patients with Sertoli cell only syndrome (germinal cell aplasia), severe hypospermatogenesis, tubular hyalinization. germinal cell arrest, and Leydig cell failure were not always in response to the medical therapy. 8. There have been wide variations on reported normal range of spermiogramme(Table 7). The lower limits of spermiogramme which is necessary to impregnate have been reported that sperm count. more than 20X106/ml and 100X 106/total; motility, more than 50% ; normal morphology, more then 70%, despite patients with sperm counts less than 1X106/ml could impregnate in 11% of them (Table 8). However, the author`s experience suggested that for the successful pregnancies to take place, the following conditions must be met in the volume of 2ml of seminal fluid, the sperm count, more than 40X106/mI, 60% of motility with 3 of activity grade, and 80% of normal morphology (Tables 9 and 10). Marked fluctuations in sperm count (fluctuation range, 100X 106/ml) are observed in both normal and infertile males. therefore, at least 3 semen analyses should be carried out before the treatment. This clinical observation showed that significant improvement could be traced especially in patients with the sperm counts of pre-treatment were exceeded 10X 106/ml. 9. Plasma FSH, LH, and testosterone should be measured in cases of small testis with severe oligospermia, and azoospermia. Infertile patients with extremely high FSH Level, hypergonadotropic hypogonadism, was not responded to the medical therapy(Tables 11, 12, 13, 14 and Fig. 1). 10. There is suggestive evidence that the combined use of 5 different regimens such as HCG, Testosterone, Liothyronine, L-Arginine, and AICAMIN in the forms of continuous medication at least for the period of 3 months, seems to be more effective than any others. However, this evidence was not conclusive since it has been noted that with some medications, the deteriorated effect was greater than the improved effect. 11. It has been reported that improvement was found in about 30% of the patients and pregnancy occurred in about 10% of the patients who were treated (Tables 15 and 16). However, pregnancy occurred in the 15 men out of the 51 patients whose spermigoranme improved with the medical therapy, whilst pregnancy resulted in the 4 men out of the 96 patients whose spermiogramme unchanged. and also pregnancy took place in the 2 men out of the 29 patients whose spermiogramme deteriorated in the oligospermia group of the present series. This pregnancy rate raises considerable doubt as to the efficacy of the empirical therapy in treating men with infertility, was medical treatment more successful than no treatment). 12. It is very difficult to judge properly the efficacy of the medical therapy without control group of men with placebo and without well controlled trials with an adequate data. A far more precise diagnosis procedures, selection of strict indications end selection of an appropriate treatment regimens should be necessary to evaluate properly the usefulness of the treatment. Further studies with increased number of patients for development of fundamentals of such medical treatment and also standardization of protocol for international comparisons.