CLOMIPHENE THERAPY IN MALE INFERTILITY: A NEGATIVE REPORT"

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1 FERTILITY AND STERILITY Copyright 1979 The American Fertility Society VoL 32, No.5, November 1979 Printed in U.8A. CLOMIPHENE THERAPY IN MALE INFERTILITY: A NEGATIVE REPORT" CHARLES W. CHARNY, M.D.t Department of Urology, Albert Einstein Medical Center, Philadelphia, Pennsylvania The enthusiastic acceptance of the use of clomiphene citrate in the treatment of the subfertile male prompts the issuance of this report. Fifty-four subfertile males were treated following recommended guidelines. In addition, testicular biopsy was performed in each patient. Analysis of the results, even excluding those with elevated follicle-stimulating hormone levels (which everyone concedes spells a poor prognosis), shows only a small percentage of improvement. Fertil Steril32:551, 1979 The administration of clomiphene citrate elicits ovulation in a relatively large percentage of anovulatory women. Huppert and Wallach 1 stated that "ovulation can be anticipated in approximately 75% to 80% of cycles." Rust et al,2 reported a 91.4% ovulation rate and a 38.1% pregnancy rate. In a more recent article, Wallach 3 stated that "in properly selected patients [italics mine] ovulation can be expected to occur in response to clomiphene with a 70% frequency" and that pregnancy occurs "in the vicinity of 50%." The favorable response in women is brought about through a release of gonadotropic hormones in appropriate sequence. Women with pituitary insufficiency (low levels of follicle-stimulating hormone [FSH]) do not respond to clomiphene. The favorable results following the use of clomiphene citrate in anovulatory women served as a prelude to its use in men. Many early investigators employed the drug in varying doses, some very high, with indifferent results. Jungck et au reported a variety of results with some stimulation and some suppression. Their dosage was obviously too high. This was followed by other reports. 5 In Received February 3,1979; revised May 18, 1979; accepted July 12, *Presented at the Thirty-Fifth Annual Meeting of The American Fertility Society, February 3 to 7, 1979, San Francisco, Calif. tsenior Attending Urologist, Emeritus. Reprint requests: Charles W. Charny, M.D., 2039 Delancey Street, Philadelphia, Pa , Heller et al. 6 reported the results of relatively large doses-50 to 700 mg daily-in normal male volunteers. They demonstrated increased urinary excretion of gonadotropins in all of the subjects even when there was no improvement in semen. Of eight volunteers treated, there were increases in sperm count in three, moderate decreases in two, and precipitous decreases in the other three. They concluded that clomiphene citrate evoked two actions on the germinal epithelium-a preliminary stimulation and a secondary inhibition, generally observed with the higher doses. The stimulatory effect resulted in an increased division of spermatogonia. The toxic effect which occurs with high doses is directed at the mature spermatids, many of which are abnormal and are "resorbed during passage through the tubular system." It is important to emphasize that the clomiphene citrate was given to fertile males with a normally functioning germinal epithelium. Such cells are conditioned to respond to proper stimulation. Cells which are part of disturbed spermatogenesis do not necessarily respond in the same manner. Kastin et au noted an increased release ofluteinizing hormone (LH) after the administration of LH-releasing hormone to subfertile men pretreated with clomiphene. They reported that ingestion of clomiphene for 8 days resulted in a significant increase in serum LH and FSH concentrations which did not further increase after another 8 days. If that observation is correct, is there, 551

2 CHARNY 552 then, some doubt that the continued administration of clomiphene for a prolonged period of time may produce a limited stimulation which will not increase with further ingestion of clomiphene? Many other clinical reports have appeared on the effect of clomiphene in the male. 8 Tyler et al. 9 found "no significant change in count." Santen et al. 10 observed stimulation of pituitary gonadotropin secretion and testosterone in normal men but no effect in those with hypogonadotropic hypogonadism, i.e., with low FSH levels. Schellen and Beekl l treated 101 men and had only 40 total failures. However, of those designated "improved," sperm counts in 45 barely reached 5 million/ml and in 20 others the counts rose to only 10 million/ml. Of the pregnancies that followed, eight occurred in wives whose husbands' sperm counts did not exceed 5 million/ml. Wieland et al,12 treated 11 men with small doses of cisclomiphene-either 5 or 10 mg daily for 12 weeks. They concluded that "increases in sperm count occur... in an unpredictable fashion." Foss et al. 13 treated 114 subfertile men and found "no consistent improvement." Impetus to the use of clomiphene in men was accelerated by the publications of Paulson et al which stressed the importance of low dosage and reliance on FSH determinations. They reported improvement in 45 of 57 men whose seminal abnormality was secondary to "hypothalamic or pituitary dysfunction"-normal FSH levels. The results were poor in those with low FSH levels and those with primary germinal hypoplasia (high FSH levels). To quote Paulson et al. 14: "When hypofertile states are secondary to either hypothalamic or pituitary dysfunction and not to endorgan pathology, enhanced gonadotropin release should initiate positive therapeutic change." Many more reportsl7. 18 on the use of clomiphene citrate followed, most of them favorable. My experience with the use of clomiphene dates back to The results were poor, possibly because the dosage was excessive (50 to 100 mg daily) and the period of treatment was relatively short (2 to 3 months). These results were not reported at that time, nor are they included in this report. November 1979 lion/ml, 18 had counts less than 5 million/ml, and 2 had azoospermia. All had poor sperm motility, and 47 had abnormal morphology. Radioimmunoassay determinations of FSH, LH, and testosterone levels and testicular biopsies were performed for each man before treatment. The clinical advantage of preliminary testicular biopsy is demonstrated by the exclusion from this series of four men with counts of 1 million or less whose biopsies showed aspermatogenesis in all but a few tubules. Testicular Biopsy. All biopsies revealed lesions that, by previous definition, should respond to treatment if available; that is, lesions which appeared reversible with healthy development to at least the spermatocyte stage without hyalinization or fibrosis. A uniform histologic picture is most important. Biopsies which show only islands of normally functioning tubules surrounded by small functionless tubules spell a poor prognosis. For this reason, a generous piece of tissue-not less than 3 mm in diameter when fixed and stained-is essential. I am well aware of the feeling of many clinicians that biopsy is of value clinically only to differentiate between obstructi ve and nonobstructive azoospermia. Biopsy is of greater value clinically: witness two instances of azoospermia in which biopsy yielded sufficient information to permit rational evaluation and clinical management (Figs. 1 and 2). FSH Levels. FSH levels are shown in Table 1. Of the 54 men, 5 (9%) had FSH levels under 3 miu/ml (2 with FSH of 1.0 and 1.5 mlu); 35 (65%) had normal values; 9 (17%) had moderately elevated FSH (26 to 50 miu/m!); and 5 (9%) had very high FSH (51 to 100 miu/ml or more). PATIENTS AND METHODS Selection of Patients for Treatment. Fifty-four subfertile males comprise this report. Each patient had at least two preliminary semen examinations. All but four had sperm counts less than 20 million/ml, 28 had sperm counts less than 10 mil- FIG. 1. Testicular biopsy of a 34-year-old patient with azoospermia. His FSH level was 27.7 miu/ml. Genital examination disclosed testes of normal size and consistency. Development was arrested, for the most part, at the spermatocyte level. The interstitial tissue was normal. There was no improvement after either rebound or clomiphene therapy.

3 Vol. 32, No.5 CLOMIPHENE THERAPY IN MALE INFERTILITY 553 TABLE 2. FSH Levels and Treatment Low «3 miu/m!) Before treatment Improved as previously defined Normal Elevated (5-25 miu/m!) miu/ml >50 miu/ml o "In a separate series, four patients with FSH values of 1.0, 1.5,2.3, and 2.7 miulml, respectively, were treated with Pergonal (human menopausal gonadotropin) combined with human chorionic gonadotropin after failure with clomiphene. Each improved, two achieving pregnancy. The most dramatic improvement was observed in a patient with an FSH level of 1. 0 miu/ml. These data will be reported in a future publication. FIG. 2. Testicular biopsy of a 26-year-old patient with azoospermia. His FSH level was 18.0 miulml. He had been hospitalized 1 month earlier for viral pneumonia. The section shows considerable deterioration of cytoplasm with sloughing of the germinal epithelium, and interstitial edema. No treatment was given. Spermatozoa reappeared 2 months later, and a semen examination after 3 months showed a sperm count of 72 million/ml with good motility and morphology. Note the degenerating cytoplasm of the spermatocytes as compared with the healthy cytoplasm in the specimen shown in Figure 1. Dosage of Clomiphene. Of the 54 husbands, 44 were given 50 mg of clomiphene 5 days/week and 10 received 25 mg daily. Forty-six patients received clomiphene for 3 months; 7 continued the drug for 7 to 9 months, One husband stopped taking the medication after 1 month because pregnancy intervened. RESULTS Semen. The term "improved" is applied to those patients in whom semen examination showed a sperm count of at least 20 million/ml, less than 4<1% abnormal forms, and at least 5<1% actively motile. By these criteria, only four patients (7.5%) improved. These four patients had preliminary counts of 12.8, 15.5, 17.0, and 22.3 million/ml, respectively. All four showed improvement of count, motility, and morphology. Another seven patients experienced some improvement of sperm motility but only slight changes in sperm count and no alteration of morphology. In the others, there was no improvement of motility or morphology even when the sperm count increased somewhat. This TABLE 1. FSH Levels in Patients Treated with Clomiphene Citrate No. of patients 54 Elevated Low «3 miu/m!) Normal (5-25 miu/m!) miu/ml >50 miu/ml 5(9%) 35 (65%) 9 (17%) 5(9%) was observed particularly in patients whose pretreatment counts were above 20 million/ml. The 11 patients showing even slight improvement had normal pretherapeutic FSH levels (5 to 25 mlu/mi). Those with either low or high FSH levels uniformly failed to show improvement (Tables 2 and 3). Pregnancy. One pregnancy followed improvement of semen quality as previously defined. Two pregnancies occurred following the administration of clomiphene for 3 and 9 months, respectively, without apparent improvement in semen. One pregnancy occurred in the wife of a patient whose initial sperm count of 13.2 million/ml was not altered by clomiphene, nor was the motility of 4<1% (grade 2) improved, Treatment had been continued for 6 months. The last three semen examinations at monthly intervals averaged counts of 14.4 million/ml with 4<1% (grade 2) motility-a semen picture somewhat similar to the average pretreatment examinations. One pregnancy occurred during the 1st month's treatment with clomiphene. Unfortunately, the patient would not submit another semen specimen for examination. DISCUSSION There is general agreement that the favorable outcome following the administration of clomiphene citrate results from hyperstimulation of the hypothalamus. Such a reaction apparently occurs only when there is normal hypothalamic function. 3 A low FSH level is indicative of hypothalamic hypofunction,21.22 and such patients do not respond to clomiphene. A high FSH level implies inability of the gonads to inhibit hypothalamic secretion. In such patients the lesion is primary hypospermatogenesis, i.e., the sperm-producing tissue lacks the capacity to respond to stimulation.

4 554 CHARNY November 1979 TABLE 3. Improvement after Clomiphene Treatment Patient Count miuionjml Before treatment Motility % Grade Duration of treatment M.R M.K R. B J.H mo Dosage After treatment Count Motility % Grade millionjml 50 mg 5 X wk mg daily mg 5 x wk mg 5 x wk This lack of capacity is most probably present even in some subfertile males with normal FSH levels and may account for the high percentage of failures with clomiphene. In my series, improvement induced by clomiphene was observed in those men with the least amount of spermatogenic suppression. Patients with very low counts (under 5 million/ml) showed very little tendency to respond to clomiphene. The difference in improvement between the male and the female is again evident. Even the most optimistic reports on the use of clomiphene in the male do not compare favorably with the high percentage of good results elicited in the female. It has been stated repeatedly by the author 19 in discussions of faulty spermatogenesis as viewed by testicular biopsy that the spermatogenic tissue is most sensitive to toxic or environmental factors and that many lesions of spermatogenic tissue resulting in reduced fertility are not endocrine-induced and are not improved by endocrine therapy. Primary spermatogenic failure is apparently more common than was supposed. Peritubular thickening, whether fibrous or hyaline, is often associated with a reduction of the number of spermatogonia lining the basement membrane. Even though Heller et a1. 6 observed increased division of spermatogonia with clomiphene, none of the patients in this series who showed even very mild peritubular hyalinization experienced improvement. Also, to repeat, the volunteers in the study by Heller et a1. 6 had normal spermatogenic tissue with adequate capacity to respond to stimulation. It has been called to my attention that the discrepancy between the results reported herein and the results of those reporting more frequent improvement may be due to my definition of improvement, i.e., a minimal sperm count of 20 million/ml with good motility and satisfactory morphology. This may be a point worthy of debate in view of the recent re-emphasis by MacLeod and Wang 23 of the importance of good motility. How- ever, there is little justification for crediting treatment if pregnancy occurs soon after recent semen examinations displaying poor motility as well as low count, nor is a pregnancy resulting 1 year or more after therapy has been discontinued necessarily the result of treatment. CONCLUSI0NS 1. In this series the use of clomiphene in the subfertile male has not yielded the good results recently reported by others. 2. Even if the high standards for improvement as promulgated here were lowered to include in the improved group those whose semen quality had improved only slightly, the total percentage ofimprovement is still less than 21%. 3. The failure ofthe male to respond to hormone therapy in the dramatic manner of the female must lie in the nature of the lesions responsible for male and female subfertility. 4. Testicular biopsy studies point to degenerative lesions, possibly nonhormonal, as a cause for many instances of depressed spermatogenesis. 5. This presentation is not intended to discourage the use of clomiphene in the male. However, further investigation is necessary before the administration of clomiphene citrate can be adopted as routine treatment and employed without complete pretherapeutic investigation. REFERENCES 1. Huppert LC, Wallach EE: Induction of ovulation with clomiphene citrate. J Reprod Med 18:201, Rust LA, Israel R, Mishell DR Jr: An individualized graduated therapeutic regimen for clomiphene citrate. Am J Obstet GynecoI12:785, Wallach EE: Recent advances in infertility. Philadelphia Med 75:167, Jungck EC, Greenblatt RB, Mahesh VB: Effect of clomiphene citrate on spermatogenesis in the human. Fertil Steril 15:40, Melinger RC, Thompson RS: Effect of clomiphene citrate in male infertility. Fertil Steril 17:94, 1966

5 Vol. 32, No.5 CLOMIPHENE THERAPY IN MALE INFERTILITY Heller CG, Rowley MJ, Heller GV: Clomiphene citrate: an evaluation of its effect on sperm concentration and morphology, total gonadotropins, ICSH, estrogen and testosterone excretion and testicular cytology in normal men. J Clin Endocrinol Metab 29:638, Kastin AJ, Schally AV, Gual C, Midgley AR, Miller MC, Floris F: Increased release of LH after administration of LH-RH to men pretreated with clomiphene. J Clin Endocrinol Metab 31:689, Mroueh A, Lytton B, Kase N: Effect of clomiphene citrate on oligospermia. Am J Obstet Gynecol 98:1033, Tyler ET, Winer J, Gotlib M, Olson HJ, Nakabayashi N: Effects of MRL-41 in human male and female fertility studies. Clin Res 10:119, Santen RJ, Leonard JM, Sherins RJ, Gandy HM, Paulsen CA: Short and long term effects of clomiphene citrate on the pituitary testicular axis. J Clin Endocrinol Metab 33:970, Schellen TMCM, Beek JJHMJ: The use of clomiphene treatment for male sterility. Fertil Steril 25:407, Wieland RG, Ansari AH, Klein DE, Dishi NS, Halbert MC, Chen JC: Idiopathic oligospermia: control observations and response to cisclomiphene. Fertil Steril 23:471, Foss GL, Tindall VR, Birkett JP: The treatment of subfertile men with clomiphene citrate. J Reprod Fertil32:167, Paulson DF, Wacksman J, Hammond CB, Wiebe HR: Hypofertility and clomiphene citrate therapy. Fertil Steril 26:982, Paulson DF, Wacksman J: Clomiphene citrate in the management of male infertility. J Urol 115:73, Paulson DF: Clomiphene citrate in the management of male hypofertility: predictors for treatment selection. Fertil Steril 28:1226, Epstein JA: Clomiphene citrate in oligospermic infertile men. Fertil Steril 28:741, Check JH, Rakoff AE: Improved fertility in oligospermic males treated with clomiphene citrate. Fertil Steril28:7 46, Charny CW: Treatment of male infertility. In Progress in Infertility, Edited by SJ Behrman, RW Kistner. Boston, Little, Brown and Co, 1968, Chap Charny CW: The male factor in barren marriages. In Diagnosis and Treatment of Menstrual Disorders and Sterility, Edited by SL Israel. New York, Hoeber, 1967, Chap Wu CH: Plasma hormones in clomiphene citrate therapy. Obstet Gynecol 49:443, Wu CH: Monitoring of ovulation induction. Fertil Steril 30:617, MacLeod J, Wang Y: Male fertility potential in terms of semen quality: a review of the past, a study of the present. Fertil Steril 31:103, 1979