TESTOSTERONE REBOUND THERAPY: A NEGLECTED MODALITY*

FERTILITY AND STERILITY Copyright ~ 1978 The American Fertility Society Vol. 29, No.1, January 1978 Printed in U.S.A. TESTOSTERONE REBOUND THERAPY: A NEGLECTED MODALITY* CHARLES W. CHARNY, M.D.t JULIAN A. GORDON, M.D.:\: Albert Einstein Medical Center, Philadelphia, Pennsylvania 19141, and Naval Regional Medical Center, Philadelphia, Pennsylvania 19145 A summary of the literature and a 20-year review of our own experience with testosterone rebound therapy is presented. Of 225 patients followed, 52% rebounded to fertile levels followed by pregnancy in the wives of 25%. Pregnancy occurred in 3 wives (8%) of the 38 initially azoospermic patients. There was only a 4% incidence of failure to return to at least the pretreatment sperm count following therapy, and no persistent azoospermia was observed. These results are consistent with other recent reports of several large series of patients. Proper screening and selection of patients is mandatory. Testosterone rebound is a neglected form of therapy meriting consideration in selected patients. Despite the rapid progress in the endocrine management of the infertile female, relatively little has been accomplished in the male. Whatever the explanation for this, the fact remains that only a small percentage of infertile males are improved by specific endocrine therapy. Endocrines which have been employed in the male include thyroid (Cytomel),1 glucorticoids,2 low-dose testosterone,3-6 high-d~se androgens such as mesterolone,7 human chorionic gonadotropin,8.9 human menopausal gonadotropin,1o.11 and clomiphene citrate. 12.14 Some of these agents still have their proponents, whereas others have been discarded. Testosterone rebound therapy, which enjoyed popularity when Heller et au5 first promoted its use in 1950, has oflate fallen from grace. It has, however, received continued support from a number of clinicians as evidenced by the reports of Heckel and Mac Donald,16 Charny, 6. 17 Spence and Medvei,18 Received April 18, 1977; revised July 22,1977, and August 25,1977; accepted August 25, 1977. *Presented at the Ninth World Congress on Fertiltiy and Sterility and the Thirty-Third Annual Meeting of The American Fertility Society, April 12 to 16, 1977, Miami Beach, Fla. t Albert Einstein Medical Center. Reprint requests: Charles W. Charny, M.D., 2039 Delancy Street, Philadelphia, Pa. 19107. :\:Naval Regional Medical Center. 64 Rowley and Heller,19 Joel,20 Lamensdorf et al.,21 and Paulsen.22 SELECTION OF PATIENTS FOR REBOUND THERAPY All patients treated met the following criteria: History. No patient had a history of serious prepuberal or puberal illnesses, of having been treated for delayed puberty or cryptorchism, or of orchitis or epididymitis. No patient had been unduly exposed to diagnostic or therapeutic radiation. Most important, the patient's wife had no deterrent to pregnancy. Physical Examination. Each patient had testes of normal size and consistency with no gross evidence of endocrinopathy. Semen. Most patients had sperm counts of less than 10 million/ml. Of the 440 men treated, only 41 had higher sperm counts. Along with the reduced sperm counts, most patients had poor motility (0% to 30%) and abnormal morphology (more than 40%). Radioimmunoassay. Radioimmunoassay was performed when it became available, particularly of follicle-stimulating hormone (FSH). Only patients with normal or elevated FSH levels were treated. Those with low FSH levels (less than 2 miu/ml) were treated with menotropin (Pergonal),

Vol. 29, No.1 TESTOSTERONE REBOUND THERAPY 65 with or without chorionic gonadotropin, with uniformly good results. 23 Testicular Biopsy. A testicular biopsy was performed in every patient.* Only those men who had "reversible" lesions were treated by rebound therapy. A reversible lesion was defined as one showing a uniform histologic picture with seminiferous tubules of normal size with good staining although showing incompletely matured spermatogenic epithelium without sclerosis, hyalinization, or fibrosis. METHOD OF TREATMENT Four hundred and forty patients were treated during the last 20 years. In the early years of the study, prior to the introduction of long-acting testosterone, the patients received 50 mg oftestosterone intramuscularly three times per week. Subsequently, long-acting testosterone was used. Testosterone enanthate was used in 152 patients and testosterone cypionate in 208 patients. The dosage was 200 mg intramuscularly weekly for a period of 20 weeks. If azoospermia occurred early, the dosage was reduced to 200 mg every 2 weeks. If azoospermia did not occur within 10 weeks, the injections were continued weekly but the dosage was reduced to 100 mg. Forty patients were treated by following the technique of Rowley and Heller.19 Nilevar (17aethynyl-19-nortestosterone, a progesterone-like drug), 10 mg orally every 12 hours, was given for 10 weeks. This dosage was supplemented by intramuscular testosterone cypionate, 200 mg on the 1st, 22nd, and 50th days, in order to counteract any side effects from the Nilevar. The semen examination was repeated every 4 weeks. RESULTS Of the 440 patients treated, 185 were lost to follow-up; that is, either they did not return with semen specimens after the injections were stopped or they failed to return after 2 months. Two hundred and fifty-five patients were followed for 6 to 12 months or more. The results are shown in Table 1. A rebound to a fertile level was defined as one in which (1) the sperm count rose to at least 20 million/ml; (2) morphologic study showed fewer than 40% abnormal sperm; (3) at least 50% ofthe sperm were actively motile; and (4) such rebound lasted for at least 3 months. Of the 133 patients who improved, 4 were initially azoospermic, 74 began with sperm counts of less than 5 million/ml, 33 began with sperm counts between 5 and 10 million/ml, and 22 began with sperm counts of 12 to 18.2 million/ml. Four patients receiving testosterone showed only initial stimulation rather than suppression after four intramuscular injections. This stimulation resulted in "fertile" specimens. Pregnancy occurred in the wives of two of these men within 2 months, and testosterone administration was stopped. In the other two men, further testosterone therapy resulted in suppression to azoospermia with ultimately satisfactory rebound. Pregnancy occurred in one of the two wives. Of the patients followed, 217 were oligospermic; 129 (60%) rebounded and 62 (29%) achieved pregnancy. Of 38 who were initially azoospermic, 4 (11%) had a satisfactory rebound and 3 (8%) achieved pregnancy (see Table 2). It should be noted that one patient originally azoospermic fathered three children after repeated courses of rebound therapy, but this result was recorded statistically as one pregnancy. One other successfully treated azoospermic patient subsequently sired one child. Of the 34 remaining azoospermic patients, 7 who were considered failures because the semen quality did not reach a fertile level showed sperm counts of 0.5 to 4 million/ml at the height of the rebound and only 3 of these 7 returned to an azoospermic state. Duration of Improvement. The rebound to fertile levels was observed within 3 to 4 months following cessation of therapy. The duration of improvement was as follows: of the 133 patients with satisfactory rebound, 111 (84%) remained improved for only 2 to 3 months, 13 (10%) for 4 to 6 months, and 9 (7%) had sustained improvement Diagnosis No. of patients TABLE 1. Results of Rebound Therapy Improved semen No. % Oligospermia 217 129 60 Azoospermia 38 4 11 Total 255 133 52 Pregnancy achieved Decreased coun t No. % No. % 62 29 9 4 3 8 65 25 9 4 *Six successfully treated patients consented to a second biopsy which showed definitely improved spermatogenesis,

66 CHARNY AND GORDON January 1978 TABLE 2. Duration of Improvement in Patients Who Rebounded 2-3 Mo 4-6 Mo >6Mo No. of patients No. % No. % No. % 133 111 84 13 10 9 for the entire period of observation (12 months or more) (see Table 2). In those patients who were treated with Nilevar and testosterone, regeneration with at least a return to pretreatment levels was observed the next month. The percentage of improvement with Nilevar was slightly better, and the duration of improvement was considerably prolonged. Of these 40 patients, 24 (60%) rebounded. Ofthese 24 patients, 11 showed improved semen quality during the period of observation, which av~rage~ 9 months. Four patients apparently remamed Improved for an indefinite period, second pregnancies occurring without further treatment. Repeat courses of therapy were administered 12 times to patients whose rebound was of too short a duration to achieve pregnancy or to those patients who achieved pregnancy and later wanted another child. Two of those who did not rebound the first time rebounded adequately the second time with resultant pregnancies. Four patients did not demonstrate a satisfactory rebound, but pregnancies nonetheless occurred. Five of these patients had initial sperm counts under 5 million/ ml and two patients had counts between 7 and 9.5 million/ml. Sperm counts at the height of rebound varied from 10.2 to 14.5 million/ml. However, the sperm motility approached normal levels. Complications. One patient reported weight gain because of water retention which was remedied by diuretics. Failure to return to the pretreatment level was observed in nine patients (4%), but none remained azoospermic. All ofthese patients had very poor pretreatment semen quality (none had a sperm count higher than 1.5 million/mi). Comparison of This Report with Others Recently Published. Rowley and Heller19 reported a 68% increase in the sperm counts of 163 men and a 41% pregnancy rate. Those with increased counts remained in the improved range from 6 months to 4 years. Of those who did not respond, 8% decreased their count to 60% of the original level but none remained azoospermic. It should be noted that Rowley and Heller19 defined an improved sperm count as one in which there was an increase of at least 25% above the pretreatment level. 7 Joel,20 in his series of 73 patients receiving a variety of testosterone doses, reported an improvement of semen quality in 13.7% and a 6.8% pregnancy rate. He reported an 8.8% deterioration rate. The most recent report is that of Lamensdorf et al.,21 who reported 145 patients. They did not perform testicular biopsies as part of the screening procedure or an endocrinologic evaluation unless a specific lesion was suspected. The dosage used was 100 mg (occasionally 200 mg) of testosterone cypionate for 20 weeks. Lamensdorf et al,21 reported a 29% pregnancy rate (38 of 131) for oligospermic men and an 8% pregnancy rate (1 of 12) for azoospermic men, with an over-all pregnancy rate of 27%. Of those who had followup semen analyses, 47% had improved semen; however, of 45 men whose semen did not improve, 7 nevertheless achieved pregnancy. In that series, there was a 2% incidence (three patients) of permanent azoospermia (see Table 3). A prolonged increase in sperm count (lasting for 3 to 4 years) was noted by Rowley and Heller,19 and in our series a permanent increase was noted in 7% of those who rebounded. However, the majority of those who respond do so for only 3 to 4 months. It should be noted that the rebound effect is reproducible andean be repeated a number of times. It has also been our observation that frequently the repeat course of therapy, begun soon after the semen returns to the pretreatment level, results in a degree of rebound even greater than the first. Thus, this treatment can be repeated if the first course of therapy does not result in a sufficiently improved quality or if more children are desired. DISCUSSION The rebound phenomenon is a nonspecific reaction based on a long-accepted biologic principle. In its reaction to injury, the body not only restores the tissue that has' been damaged, but, temporarily at least, overproduces this tissue in an TABLE 3. Collected Review of Recent Literature No. of % % Of Author patients Improved pregnancies" Joepo (1960) 73 13.7 6.8 Rowley and Hellerl9 163 68 41 (1972) Lamensdorf et al. 21 145 47 290 (1975) 8A 27 T Charny and Gordonb 255 52 290 (1978) 8A 21 T "0, Oligospermia; 'A, azoospermia; T, total. bthis paper. % Decrease in count 8.8 8 2A 4

Vol. 29, No.1 TESTOSTERONE REBOUND THERAPY 67 attempt to ensure proper repair. In the series reported here, the preliminary depression of spermatogenesis was induced by testosterone, but other agents may be used for the same purposewitness the group of patients who received a progesterone-like product such as Nilevar, or even the larger series of patients treated with Nilevar, as reported by Rowley and Heller.19 Testosterone produces no untoward effect and may even stimulate spermatogenesis during the preliminary period of treatment. The improvement of semen quality-to a fertile level-in four men who received an average dose of 800 mg of testosterone over a period of 4 weeks is an interesting sidelight. A re-evaluation of the pretreatment testicular biopsies and the radioimmunoassays fails to account for such a reaction. Reports of semen improvement following the oral administration of small doses of testosterone 5 6 fall into the same category. A favorable response to testosterone adminii;lfration in men who have no testosterone deficiency defies explanation, at least for the present. The fact that they respond rapidly (within 1 month) is not unreasonable because the patients' spermatogenic development may have surpassed the spermatocyte level, and development from the spermatid to spermatozoon level requires only a fraction of the 64 days for the entire process. Admittedly, rebound therapy is an unsatisfactory method of treatment for the following reasons: 1. We are unable to select, specifically, patients suitable for treatment. 2. The time required for treatment is long, usually 20 weeks, followed by 4 to 6 months of observation. 3. The duration of realistic improvement is short in most patients. Patient Selection. Selection of patients for rebound therapy can be improved through careful evaluation of a preliminary testicular biopsy. The histologic picture and the semen findings cannot generally be correlated, but the condition of the spermatogenic tissue and its chances to respond to favorable stimulation can be determined fairly accurately. To be sure, healthy spermatogenic epithelium, such as that observed in spermatocytic arrest, may not respond and that is what accounts for at least some of the failures. Length of Treatment. Originally, testosterone administration was stopped as soon as azoospermia was observed. The rebound was generally not as vigorous as that resulting from increased dosage. This fact was brought home more strikingly in those in whom Nilevar was used as the spermatogenic depressant. Azoospermia was observed early, but a greater rebound occurred in those men who continued the program to its completion. Short Duration of Rebound. This is a handicap that has thus far not been overcome. Clomiphene has been given to patients for 2 to 3 months after testosterone was stopped. Others have been given clomiphene when the semen quality showed progressive decline following the rebound peak, but the results have been disappointing. Rebound therapy is now advised only for those men whose wives possess good fertility so that pregnancy can be expected in the average 3-month period of good semen quality. On occasion, the referring gynecologists have prescribed clomiphene for the wives beginning 1 to 2 months after testosterone was stopped. In spite ofthese shortcomings, rebound therapy is still an acceptable mode of treatment. Of the patients evaluated in the past 20 years, only 18% were candidates for surgery, including high spermatic vein ligation for varicocele, epididymo~ vasostomy for obstructive azoospermia, vasovasostomy, scrotal exploration in azoospermic men with normal biopsies without evidence of obstruction, spermatocelectomy, and unilateral epididymecto my in an attempt to eliminate the alleged sources of overwhelming spermagglutination. If those men (14%) who will not respond to treatment are also excluded-those with small testes (including those with Klinefelter's syndrome), primary hypogonadism, bilateral cryptorchism, unilateral cryptorchism with contralateral hypoplasia, and congenital absence of vasa-there remains only a small percentage of patients for whom specific therapy is available. This group includes patients with hypothyroidism and hypogonadotrophic hypogonadism (low FSH). The remainder, well over 50% of the patients, have spermatogenic lesions which are not amenable to known treatment. It is the improvement of fertility in these men, even of short duration, which is compelling. The thought that pregnancy would not have occurred without treatment leads to the conclusion that rebound therapy should be used as a mode of treatment in carefully selected men until a better method becomes available. REFERENCES 1. Taymor ML, Selenkow HZ: Clinical experience with L triiodothyronine in male infertility. Fertil Steril 9:560, 1958

68 CHARNY AND GORDON January 1978 2. Jefferies WMcK, Weir WC, Weiss DR, Prouty RC: The use of cortisone and related steroids in infertility. Fertil Steril 9:145, 1958 3. Harvey C, Jackson MH: Intermittent methyltestosterone therapy in male subfertility. Lancet 1:711, 1957 4. Swyer GIM: Effects of testosterone implants in men with defective spermatogenesis. Br Med J 2:1080, 1953 5. Charny CW: In Diagnosis and Treatment of Menstrual Disorders and Sterility, Fifth Edition, Edited by SL Israel. New York, Hoeber-Harper and Row, 1967, p 552 6. Charny CW: The use of androgens for human spermatogenesis. Fertil Steril 10:557, 1959 7. Schellen TMCM, Beek MJHA: The influence of high doses of mesterolone on the spermiogram. Fertil Steril 23:712, 1972 8. Dorner G, Moch G, Zabel H: The "overproduction effect" ofthe testes after cessation ofhcg administration in men with oligospermia. Fertil Steril 11:457, 1960 9. Amelar RD: Male infertility, current diagnosis and treatment. Urology 1:1, 1973 10. Lytton B, Mroueh A: Treatment of oligospermia with urinary menopausal gonadotropins. Fertil Steril 17:696, 1966 11. Lunenfeld B, Mor A, Mau H: Treatment of male infertility. I. Human gonadotropins. Fertil Steril18:581, 1967 12. Heller CG, Rowley MJ, Heller CV: Clomiphene citrate: a correlation of its effect on sperm concentration and morphology, total gonadotropins, ICSH, estrogen and testosterone excreted and testicular cytology in normal men. J Clin Endocrinol Metab 29:638,1969 13. Mellinger RC, Thompson RJ: The effect of clomiphene citrate in male infertility. Fertil Steril 17:94, 1966 14. Paulson DF, Wacksman J, Hammond CB, Wiebe HR: Hypofertility and clomiphene citrate therapy. Fertil Steril 26:982, 1975 15. Heller CG, Nelson WO, Hill IC, Henderso~ E, Maddock WO, Jungck EC: Improvement in spermatogenesis following depression of human testes with testosterone. Fertil Steril 1:415, 1950 16. Heckel NJ. MacDonald JH: Rebound phenomenon of the spermatogenic activity of human testis following administration oftestosterone proprionate. Fertil Steril3:49, 1952 17. Charny CW: Treatment of male infertility with large doses of testosterone. JAMA 160:98, 1956 18. Spence A W, Medvei VC: Testosterone in defective spermatogenesis. Lancet 1:124, 1959 19. Rowley MJ, Heller CG: The testosterone rebound phenomenon in the treatment of male infertility. Fertil Steril 23:498, 1972 20. Joel C: The spermiogenetic rebound phenomenon and its clinical significance. Fertil Steril 11:384, 1960 21. Lamensdorf H, Compere D, Begley G: Testosterone rebound therapy in the treatment of male infertility. Fertil Steril 26:469, 1975 22. Paulsen CA: Personal communication 23. Charny CW: Unpublished data