Treatment of Oligospermia with Large Doses of Human Chorionic Gonadotropin A Preliminary Report S. J. GLASS, M.D., and H. M. HOLLAND, M.D. BEFORE discussing gonadotropic therapy of oligospermia, it is essential to make some general observations. Treatment of oligospermia remains largely empirical because the etiology is still obscure. However, certain potential causes are being brought to light. For example, Macleod 1 observed andreported recently that stresses such as viral infections and even severe allergic reactions may have profound depressing effects on spermatogenesis, which recovers eventually. But no one can predict which subject will sustain some permanent impairment of reproductive physiology as a sequel to various stresses which plague man. Another elusive potential cause of functional infertility is that of undiagnosed hepatic insufficiency. It is now well established that the liver plays a dominant role in reproductive physiology. 2 This factor assumes greater importance in the face of a rising incidence of infectious hepatitis and alcoholism. Gametogenesis depends on the functioning of a normal pituitary-gonadal axis (Fig. 1). This endocrine apparatus is keenly attuned to precise ratios of circulating sex steroid hormones. These sex hormones are conjugated in the liver. Failure to conjugate and inactivate efficiently the sex steroid hormones will inevitably influence pituitary-gonadal function with variable adverse effects on fertility. Cirrhosis of the liver eventually sterilizes the individual (Fig. 2). Because of these considerations, it is incumbent upon the clinician to search diligently for any stressful situations in the history of all infertile patients. It is unfortunate that current tests of liver function are not sensitive enough to detect the less serious degrees of hepatic insufficiency. However, Presented at Ninth Annual Meeting of the Canadian Society for the Study of Fertility, Oct. 26, 1962. The HCG used in this study was kindly supplied as A.P.L. by Dr. John B. Jewell of Ayerst Laboratories. 500
VoL. 14, No.5, 1963 501 OLIGOSPERMIA TREATMENTS we have not hesitated to treat empirically many cases of functional infertility with a nutritional regimen designed to reinforce the function of the liver as well as to render the sex end-organs more responsive to circulating sex hormones. Such a nutritional regimen should be regarded as a prerequisite to any other treatment of functional sterility. 3 ANTERIOR Fig. 1. Liver-gonadal-pituitary axis, showing importance of liver in reproductive physiology. PITUITARY \"{" GONADS :- c a [} r s s Current hormonal treatment of oligospermia usually revolves around rebound testosterone therapy. This treatment has become controversial because only a small minority of patients respond beneficially, and occasionally the azoospermia induced by testosterone becomes permanent. Our own use of testosterone in smaller doses-that is, a dose which does not induce azoospermia-gave results more beneficial than reported elsewhere. 4 A previous therapeutic trial 5 with human chorionic gonadotropin (HCG) combined with equine pituitary gonadotropin yielded some beneficial results, but antigenicity of the equine fraction limited sharply the usefulness of what appeared to be a logical treatment. The ideal combination, if it were available, would be chorionic and pituitary gonadotropin of human origin. In the absence of adequate supplies of human FSH, a therapeutic trial with doses of HCG larger than those customarily given was deemed hopeful in treating 20 men with oligospermia. There was no precise rationale for employing such treatment because s [} -.- -. [} y e., t. ;t Fig. 2. (A. J.) Testicular atrophy associated with advanced cirrhosis of liver.
502 GLAss & HoLLAND FERTILITY & STERILITY Fig, 3. (R. S.) Oligospermia with good prognosis. Hypospermatogenesis with moderate intertubular fibrosis. Fig. 4. ( R. A.) Oligosperm"fa with favorable prognosis. Hypospermatogenesis with intact tubular morphology and function. Fig. 5. (S. B.) Oligospermia and hypospermatogenesis. Note Sertoli cells with increased lipid - characteristic of impaired spermatogenesis.
ry VoL. 14, ~o. 5, 1963 tia Fig. 6. (J. A.) Oligospermia with poor prognosis. Hypospermatogenesis with extensive intertubular fibrosis. 10~r- tia yn- ld,ia is. n:ic is. OLIGOSPERMIA TREATMENTS Fig. 7. (G. T.) Oligospermia and hypospermatogenesis. Note peritubular fibrosis and thickening of basement membrane in some tubules. Fig. 8. ( S. K.) Severe oligospermia with very poor prognosis. Note architectural disorganization with extensive peritubular fibrosis. 503
504 GLASs & HoLLAND FERTILITY & STERILITY there was no demonstrable gonadotropic deficiency. However, beneficial responses do follow this treatment; therefore, it may be speculated that a supernormal gonadotropic stimulus may be required to complete or speed up spermatogenesis in cases of hypospermatogenesis or spermatogenic arrest. METHOD Twenty men with variable degrees of oligospermia were selected for the therapeutic trial. Seventeen with adequate follow-up are being reported here. Routine clinical study included determination of urinary gonadotropins as well as testicular biopsy in 6 of the subjects ( Fig. 3-8). Cases of frank hypothyroidism or eunochoidism were excluded. No biopsies were obtained after treatment was concluded. This should be done to see if the seminal cytology correlates with testicular morphology. Dosage of HCG varied from 60,000 to 180,000 I.U. given in series of 12 intramuscular injections of 5000 I.U. 2 or 3 times weekly. This dosage was arbitrarily chosen and was guided largely by the clinical responses. Because a lag in response frequently followed the treatment, each series of treatment was repeated at 2- to 4-month intervals, whenever the spermatogenic response was inadequate. RESULTS By favorable spermatogenic response is meant an improvement of 50-100% in seminal values or significant improvement in the motility and morphology without a corresponding increase in the number of spermatozoa. Occasionally these enhanced qualitative factors can make the difference between fertile and infertile semen. Table 1 shows that beneficial results were obtained in 12, with failure in 5 of the men under treatment. Of the 12 men who responded favorably, 7 wives ( 2 with 2 pregnancies) conceived and delivered 9 healthy babies. One of the 12 men was unmarried. As might have been anticipated, the failures were experienced by the men with sperm counts of less than 10 million fcc. or those with testicular atrophy or other irreversible pathology. Such patients should not be subjected to treatment because the testicular pathology cannot be reversed by any known treatment. Table 2 shows results obtained in two separate groups of 17 men with oligospermia, one treated with testosterone in small doses and the current
Y VoL. 14, No. 5, 1963 OLIGOSPERMIA TREATMENTS 505 al a TABLE 1. Results of Treatment of Oligospermia with HCG Before treatment After treatment ~d t. Sperm HCG Sperm countjm* Motile Abn. dose countj:m* :Motile Abn. Patient Age totaljml. ( o/o) (%) (I.U.) totaljml. ( o/o) ( o/o) Comment M.B. 31 126/21 60 25 120,000 175/35 85 80 Two pregnancies J. s. 47 25/10 25 50 60,000 104/52 80 25 Pregnancy W.M. e 33 48/6 80 15 120,000 350/35 75 20 Pregnancy R. A. 31 80/20 60 30 60,000 96/48 80 15 ~d Two pregnancies E. L. 30 52/17 50 45 60,000 250/60 75 10 Pregnancy R. s. 28 15/5 25 60 120,000 40/20 50 40 Pregnancy s L. S. 27 100/50 20 50 60,000 270/96 65 5 Pregnancy k D.L. 26 30/6 50 30 60,000 14/4 40 35 Unchanged ~d H.R. 31 110/22 75 20 60,000 130/26 85 20 Unchanged al N. B. 28 104/26 50 25 60,000 56/14 50 20 Unchanged S.K. 35 5/l.O 70 80 120,000 10/4 70 70 Unchanged S.B. 26 10/3.5 lo 70 120,000 2 9/3 15 20 Unchanged J. A. 27 44/22 50 40 180,000 60/90 25 20 Improved as J. F. 35 180/60 60 65 60,000 260/120 70 35 Improved D.W. 27 43/18 50 28 60,000 210/52 65 10 Improved es G.T. 22 30/15 20 25 60,000 65/35 50 10 To be married a- E. P. 26 7.5/1.5 10 30 60,000 90/1.5 50 25 *Millions. TABLE 2. Comparison of Results of Treatment with HCG and with Testosterone Treated with HCG Treated with testosterone - No. % No. ':1o r- Improved 12 70 12 70. Pregnancy 7 44 5 29 e- in group treated with HCG in large doses. Essentially similar beneficial sperma- 7 togenic responses are apparent in both groups, with the exception that more e pregnancies followed treatment with HCG. But the data are too few to carry any statistical significance. n ly DISCUSSION to n Maddock and Nelson 6 reported that treatment with HCG in a similar dosage used in our clinical trial produced Leydig-cell stimulation in both th adult men and hypogonadotropic eunuchoids, with a brisk rise in the urinary t excretion of androgens and estrogens. Furthermore, the seminiferous tubules
506 GLAss & HoLLAND FERTILITY & STERILITY showed enhanced activity in the eunochoids, whereas regressive changes were seen in the normal men. Whether our patients experienced regressive changes is unknown to us without post-treatment biopsies. But if such regressive changes did follow in our group, they must have been transitory because, after a suitable lag of 2-4 months, there was a satisfactory improvement in spermatogenesis in the majority treated by us. Could the lag in response be equivalent to rebound spermatogenesis seen after treatment with small doses of the testosterone? The role enhanced nutrition or chance effects may play in improving spermatogenesis cannot be evaluated at this time. SUMMARY Seventeen men with variable degrees of oligospermia were treated empirically with human chorionic gonadotropin ( HCG) in dosage of 60,000-180,000 I. U. Beneficial spermatogenic responses were experienced by 12 men. The wives of 7 of these men bore 9 healthy children. The failures were seen in those with sperm populations of less than 10 million fcc. The results observed here compare favorably with those obtained in another group previously treated with small doses of testosterone. Accordingly, HCG affords excellent alternative treatment to testosterone and merits a wider therapeutic trial. 360 N. Bedford Drive Beverly Hills, Calif. REFERENCES 1. MACLEOD, J. The environment in relation to the stability of human spermatogenesis. Tenth Annual meeting, Pacific Coast Fertility Society, Oct. 6, 1962. 2. GLASS, S. J. Progr. Clin. Endocrinol. 1:489, 1950. 3. GLAss, S. J. Internat. f. Fertil. 3:312, 1958. 4. GLASS, S. J., and RussELL, M. Fertil. & Steril. 3:167, 1952. 5. GLASS, S. J., et al. A. Soc. Study Steril. 77, 1947. 6. MADDOCK, W. 0., and NELSON, W. 0. ]. Clin. Endocrinol. 21:985, 1952.