The Treatment of Oligospermia with Stilbestrol and Vitamin B C. D. GOODHOPE, M.D. THE CAUSE OF OLIGOSPERMIA IS OBSCURE; the results of treatment have been questionable. But, in 1950 Culp and Beynon by mistake gave an oligospermic patient estradiol benzoate* with resulting increase in sperm count and consequent success in impregnation, and they had the good judgment to report it (Fig. 1). As a result, Herrold in 1952 reported on the use of 0.1 and 0.2 mg. stilbestrol daily for a period of 4 months. Of 39 patients, about 50 per cent showed increase in sperm count while about 50 per cent showed decrease or no change. Eight conceptions (26 per cent) occurred out of the 31 couples followed. Kearns in 1956 reported on the use of 1 mg. of ethinylestradiol daily for 30 days in 24 cases. Initially depression of sperm count was seen, followed by increased sperm count in 19, continued depression in 5, and consequent success in impregnation in 9 cases (37 per cent). MATERIALS AND RESULTS In this study 23 patients with oligospermia were treated with vitamin B12 in a dose of 25 /Lg. including the intrinsic factor, t with stilbestrolt in doses of 0.25 mg. daily for a period of 4 months. Six months after start of therapy 89.4 per cent had an increase, 10.6 per cent a decrease (Fig. 2), and the wives of 65 per cent subsequently became pregnant. Pretreatment sperm counts in this series ranged from 236,000/ cc. to 67,OOO,OOO/cc. with an average of 31,OOO,000/cc. Two months after termination of therapy, the average sperm count was 77,000,000/ cc. with no noticeable decrease in volume of ejaculate. The greatest increase was seen in a patient whose sperm count increased from 3,000,000/ cc. to 157,000,000/ cc. From Seattle, Wash. Read at the Annual Meeting of Western Section of American Urological Association, at Vancouver, B.C., June 20-23, 1960. * Progynon Benzoate. Schering Corp., Bloomfield, N. J. t Becotin with Vitamin C, Eli Lilly and Company, Indianapolis, Ind. f Kirkman Pharmacal, Seattle, Wash. 469
470 GOODHOPE FERTILITY & STERILITY All patients had been referred by gynecologists who had certified that no obvioes fault was present in the partner. Sexual abstinence for 4 days prior to semen examination was routine. Infertility had been present in this series from 12-60 months before therapy was instituted with an average duration -i ~~I ~1:Lf_II~ ~ c I I~I.. ~II~ "L- ~.. -from;- I 1 1 ~II~ ~... Fig. 1. Decrease in sperm count during Vitamin E and thyroid with subsequent increase and pregnancy after estrogenic substance was given by mistake. (After Culp and Beynon, J. Ural. 63:1093, 1950.) The patient had a record of 2 years infertility. Pregnancy was accomplished 4 months after drug therapy stopped. of 31 months, while pregnancy when it occurred happened on the average of 8.8 months, following start of treatment. Two cases, warranting special consideration are presented below. CASE REPORTS CASE NO. 1: C. B., age 25, had a record of infertility for 24 months. His sperm count before therapy was 58,OOO,OOO/cc., whereas his sperm count 6 months after start of therapy (2 months following termination of therapy) was 131,200,OOO/cc. His wife became pregnant 2 months after start of therapy. After another infertile period of 42 months, the sperm count was again found to be low. Treatment was again instituted, followed in 6 months by an increase in the sperm count and another pregnancy. A third treatment program has recently been started. CASE No.2: R. R., age 27, had a record of infertility for 48 months. The pretherapy sperm count was 30,200,OOO/cc. Six months after the inauguration of therapy, the sperm count was 97,600,OOO/cc. Pregnancy followed the start of therapy by 9 months. Another infertile period of 20 months ensued and the sperm count was again recorded as low. The treatment was repeated and was followed by a second pregnancy.
VOL. 12, No.5, 1961 OLIGOSPERMIA TREATMENT 471 One patient was advised to interrupt therapy temporarily because of breast tenderness, otherwise there has been no complaint of impotency or other undesirable side effect. 160 I... Dosage: Stilbestrol. 0.25 mg. & 812. 25,.. per day for 4 mo.... u en Z :::; 150 140 130 ** 2.. 4 YR. NO PREG. 120 110 100 90 0 80... ~ 70 ~... IU... 60 en 50 * 5 YR. NO PREG. 40 30 20 10 Fig. 2. Graphic presentation of the changes in sperm count per cc. ejaculate. Note that a decrease is seen in 2 patients of the 23, but that 1 accomplished a pregnancy. In 4 patients a post-treatment count was not made; 3 pregnancies occurred for this group. In 3 patients a post-treatment count increase was noted but not numerated, all 3 accomplished successful pregnancies. Possible Modes of Action DISCUSSION The increased fertility seen in this series does not appear to be based on a rebound mechanism, i.e. initial depression followed by a return to greater than pre-treatment levels, as was Keams' series (one 1 mg. ethinylestradiol), as nearly half of my patients impregnated their wives either while on therapy or shortly after termination of therapy.
472 GOODHOPE FERTILITY & STERILITY Observation of the lytic activity of the prostatic fluid in some of these cases using the standard fibrin plate technic of Astrup and M ullertz and. using 0.02 ml. of prostatic fluid obtained by light massage revealed that commonly the young oligospermic males' prostatic fluid will have a high lytic activity, in a range similar to that of the older man with prostatism, as compared to that of the fertile young male. Following therapy the lytic activity of the prostatic fluid of the oligospermic male may drop to the level of the normal fertile male. One might reason that a high degree of lytic activity in the ejaculate could result in too rapid liquefaction and loss, through gravity, of contact of ejaculate with cervix, thereby reducing the number of sperm in a position to travel through the cervix. The liver is capable of converting androgen to estrogen and vice versa, as well as performing its other chemical marvels. In these patients the administered estrogen may act as a ground substance which is altered according to the body's need. Estrogen is not foreign to the male blood stream. Possibly in the oligospermic patient a deficiency is present, and minimally increased blood levels of estrogen are necessary to cause the anterior pituitary control mechanism to call for increased production of gonadotrophin, to maintain a balance. It is interesting to speculate, therefore, if estmgen may playa triple role, suggested above, in aiding the oligospermic patient. Pernicious anemia is a blood disease characterized by an inability of the red cells to maturate because of the absence of available vitamin B12. Frequently, oligospermia is a disease in which there is a failure of maturation of spermatocytes. The common problem therefore in both conditions is failure of maturation. Vitamin B12 plus intrinsic factor may be acting the same way in both conditions. Secretion of the androgenic hormone is depressed in vitamin-b-deficiency.5 Herrold believes that vitamin B12 alone is of clinical value in oligospermia. Vitamin B12 therefore could be performing a dual role, increasing hormone secretion and aiding maturation. The major difference in the Herrold series and this series is the use here of oral administration of vitamin B12 with intrinsic factor. The dose of ethinylestradiol used in the Kearns' series was definitely a depressive one; the dosage used in this series was probably not. Thus, I feel, the two series cannot be compared for this reason. SUMMARY Stilbestrol in doses of 0.25 mg. with 25 flg of Vitamin B12 with intrinsic factor was given orally, daily, for 4 months to 23 oligospermic infertile males.
VOL. 12, No.5, 1961 OLIGOSPERMIA TREATMENT 473 After 6 months, 89.4 per cent had an increase in sperm count, and 65 per cent impregnated their wives after an average interval of 8.8 months from the time treatment was started. In some cases the high lytic activity of the prostatic fluid was reduced to normal levels. CONCLUSIONS The combination of small daily oral doses of stilbestrol and vitamin B12 with intrinsic factor in the treatment of the oligospermic infertile male appears to have merit and deserves wider trial. 1116 Summit Avenue Seattle, Washington REFERENCES 1. ASTRUP, T., and MULLERTZ, S. The fibrin plate method for estimating fibrinolytic activity. Arch. of Biochem. & Biophys. 40:2 p. 346, October, 1952. 2. CULP, O. S., and BEYNON, D. E. Treatment of male infertility; evaluation of medicinal therapy. ]. Ural. 63: 1093, 1950. 3. HERROLD, R. D. Influence of small doses of stilbestrol on oligospermia. J. Urol. 68:775, 1952. 4. KEARNS, W. M. The treatment of male infertility with estrogenic substance. ]. Urol. 75:852, 1956. 5. WRIGHT, S. Applied Physiology. 8th ed., Oxford, London, p. 317.