T H1s PRESENTATION concerns the extent to which specific dietary deficiencies

Transcription

1 The Relation of Dietary Deficiencies to Male Fertility Landrum B. Shettles, M.D. T H1s PRESENTATION concerns the extent to which specific dietary deficiencies may affect the male reproductive potential. Investigation has been made of the effects of diets deficient in calories, in vitamins A, B, C, and E, in minerals sodium, potassium, phosphorus, manganese, and zinc, in essential fatty acids, in protein, and in amino acids, with special reference to observations on amino acid deficiency. LACK OF CALORIES Reports on the effects of a restriction of the total food intake on the testis date back 70 years. 1 The changes observed may be summarized as follows: retardation or inhibition of development in young animals; tubular atrophy in adults, affecting chiefly the spermatozoa, next the spermatocytes and spermatids, and least of all the spermatogonia and Sertoli cells; and variable alterations in the interstitial tissue and accessory glands. 2-6 VITAMINS A, B, C, AND E The results of avitaminosis A in rats, bulls, and rams are: tubular atrophy and degeneration with sloughing of tubular epithelium, evidence of continued attempts at spermatogenesis, and epithelial metaplasia in prostatic acini and accessory glands. When vitamin A is restored to the diet, there is a rapid return to normap- 14 A series of boars fed a diet deficient in vitamin A showed normal concentrations and motility of spermatozoa. 15 From the Department of Obstetrics and Gynecology, College of Physicians and Surgeons, Columbia University, and the Sloane Hospital for Women, New York, N. Y. 88

2 Vol. 11, No. 1, 1960 DIET AND FERTILITY 89 A loss of sexual interest in man has been cited when the B complex is absent, but no morphologic changes One report on choline deficiency describes negative results. Rats fed for a few weeks a diet deficient in vitamin B developed rapid regressive changes in the male accessory glands. 20 Boars, on diets deficient in thiamin, riboflavin, nicotinic acid, and pyridoxine, had normal numbers and motility of spermatozoa. 15 Highly contradictory results have been reported concerning the effect of scurvy on spermatogenesis. For example, one worker 21 found no changes in guinea pigs dying of scurvy, whereas another 12 noted severe degenerative changes, but only in the young animals. In the rat and guinea pig the effects of vitamin E deficiency are: an early agglutination of spermatozoa in the ejaculate, a progressive degeneration involving the most differentiated germ cells first, eventually leading to complete loss of tubular epithelium, except for the Sertoli cells, and giant-cell formation from injured spermatids and spermatocytes at one stage If the deficient state is severe enough, there is a complete destruction of the spermatogonia. The irreversible injury occurs before it is morphologically detectable. These changes do not occur in the rabbit 24 or mouse 25 on a diet deficient in vitamin E. MINERALS In the experimental animal, deficiencies of the trace elements, manganese and zinc, cause atrophic changes in the tubular epithelium. In male rats on a manganese-low diet, sterility has been a constant finding. Microscopic examination reveals the absence of spermatozoa Several observers have found similar testicular changes from phosphorus deficiency. In rabbits, however, testicular changes have not been noted with manganese deficiency In deficiencies of sodium and potassium there is an impaired reproductive performance ESSENTIAL FATTY ACIDS It has been reported that rats on fat-free diets exhibit impaired reproductive performance. 33 This was noted only after the characteristic skin lesions had developed. PROTEIN DEFICIENCY Several investigations deal with a relation between the fertility rate of

3 90 SH ETTL E,S Fertility & Sterility matings in the ram, bull, boar, and rat and the protein intake It has been reported that animal proteins are more effective than vegetable proteins in this respect, which suggests that particular amino acids are concerned. Of interest in this connection are the observations made, of human subjects on a low protein intake. On subsequent questioning it was learned that these subjects had regularly witnessed a loss of sexual interest and a decreased sexual activity during the experimental period. 39 OBSERVATIONS ON AMINO ACID DEFICIENCY In studies on amino acid deficiency in healthy men between 21 and 25 years of age, the diets consisted of foods containing fat and carbohydrate plus certain fruits and vegetables, specially selected for their low protein content The protein obtained from these foods supplied approximately 10 per cent of the nitrogen intake, the remaining 90 per cent being taken independently in the form of a complete amino acid mixture in the control period, and a specifically deficient mixture in the experimental period. With the exception of the protein hydrolysate rendered deficient in the desired amino acid, the diets were most tasty and the subjects had normal appetites throughout the experiments. The nitrogen intake was fixed at 0.1 Gm. of nitrogen per Kg. per day. The total caloric intake was kept at about 2500 calories, a slight latitude being permitted in the intake of nonprotein foods. Specimens were studied of semen from 3 of the men on arginine-deficient diets. These subjects were first studied on the ninth day of the diet. They were studied again one week after the restoration of arginine, and a third series of observations was made several weeks later, after the resumption of a normal diet. The semen on the ninth day of the experiment revealed a reduction in the number of spermatozoa to approximately one-tenth the normal value, a decrease in the rate of spermatozoal locomotion and percentage of motile cells, and an increase in the number of epithelial cells and white blood cells. A diet similar but containing arginine, which followed the deficiency period, caused a prompt increase in numbers of spermatozoa; several weeks on a normal diet, however, were required before the normal values were entirely regained. 15 Although in a later study 42 no effect of arginine deficiency on human spermatogenesis was noted, another investigator 43 had given 2 Gm. of

4 Vol. 11, No. 1,1960 DIET AND FERTILITY 91 Fig. 1. X 300. Testis from paired-fed control rat. Active spermatogenesis. Reduced from -~ arginine per day for 20 to 30 days to patients with oligospermia and observed an increase in the spermatozoal count. In observations on rats fed diets deficient in single amino acids, viz., leucine, methionine, valine, lysine, tryptophane and arginine, for each experimental group of animals, paired-fed controls were studied A histologic section of the testis of a paired-fed control rat is depicted in Fig. 1, and sections from testes of the rats on the respective amino acid deficient diets are shown in Figs. 2 to 7. Figures 2, 3, and 4 indicate clearly that the absence of leucine, methionine, or valine from the diets of rats did not affect the reproductive organs or spermatogenesis, whereas the lack of lysine, tryptophan, or arginine produced moderate to marked histologic and cytologic changes in the testes, and impairment of spermatogenesis (Figs. 5, 6, and 7); these animals had a low ratio of testis to body weight; those on valine, methionine, and leucine deficiencies had a normal ratio of testis to body weight. One of the most noteworthy findings was the presence

5 Fig. 2 (top). Testis from rat on leucine-deficient diet 79 days. Active spermatogenesis. Reduced from X 300. Fig. 3 (bottom). Testis from rat on methionine-deficient diet 78 days. Active spermatogenesis. Reduced from X 300.

6 Fig. 4 (top). Testis from rat on valine-deficient diet ll5 days. Active spermatogenesis. Reduced from X 300. Fig. 5 (bottom). Testis from rat on lysine-deficient diet 52 days. Approximately normal amount of interstitial tissue. Reduction in tubule diameter. Some Sertoli cells, detached and altered in shape. No mitotic figures. Some fairly normal spermatogonia. Reduced from X 300.

7 Fig. 6 (top). Testis from rat on tryptophan-deficient diet 100 days. Interstitial tissue reduced in amount. Tubule size reduced. Sertoli cells absent or not recognizable. Cell fragments and eosinophilic material in the tubules. No mitotic figures. Reduced from X 300. Fig. 7 (bottom). Testis from rat on arginine-deficient diet 47 days. Marked cytologic changes throughout. Spermatogenic function completely gone. Note the multinucleated giant cells. Reduced from X 300.

8 Fig. 8 (top). Testis from control boar. Active spermatogenesis. Reduced from X 300. Fig. 9 (bottom). Testis from boar on tryptophan-deficient diet 74 days. Note atrophy, marked disorganization, and absence of spermatogenesis. Reduced from X 300.

9 96 S H ETTL E:S Fertility & Sterility of multinucleated giant cells in the testes of the rats on the argininedeficient diet. If the growing rat is placed on an arginine-deficient diet, demonstrable anatomic changes develop in the testes as early as the third week, and in the course of two months their disorganization becomes so complete that the tissue is scarcely recognizable; no evidence of spermatogenesis remains and the lumina of the tubules are filled with cellular debris, leukocytes, and multinucleated macrophages. 41 Although a subsequent study 44 of the rat failed to show any effect of arginine deficiency on spermatogenesis, other reports note results showing that rats on arginine-deficient diets do not have normal spermatogenesis. Thymonucleic acid has also been cited as essential for normal spermatogenesis in the raty The histologic findings in the testes of boars fed a tryptophan-deficient diet and in those of normal litter mate controls are depicted in Figs. 8 and 9. It can be noted that the pigs on the tryptophan-deficient diet showed definite testicular atrophy, marked disorganization of the testes, and absence of spermatogenesis, whereas the controls showed normal testes and active spermatogenesis. COMMENT The reports on the effects of a lack of calories must be interpreted with caution. It is by no means clear that the results were caused by caloric restriction. It is possible that they were brought about by a concomitant restriction of one or more essential vitamin, mineral, or amino acid. In none of 41 studies was the attempt made to restrict calories and yet supply the accessory food factors. It is extremely difficult to construct diets deficient in manganese, zinc, phosphorus, sodium, or potassium. Accordingly, it is not likely that such mineral deficiencies play any part in infertility of the human male. The impaired reproductive performance of rats on fat-free diets was noted only after the characteristic skin lesions appeared, which were not produced in many animals. Consequently, it is felt unlikely that fatty acids are of significance in human reproduction. In spite of the normal nitrogen balance which the 3 men maintained throughout the experimental period, it seems necessary to conclude that a temporary deficiency of arginine in the diet causes disturbance of spermato-

10 Vol. 11, No.1, 1960 DIET AND FERTILITY 97 genesis which may be related to the high arginine content of the spermatozoa; approximately 75 per cent of the nitrogen in spermatozoa consists of arginine. These findings point rather strongly to a specific relationship between dietary arginine and the integrity of the testis. During the experiment the human subjects maintained their body weight. Apparently they utilized the arginine derived from the testes for purposes of general body maintenance. This phenomenon is exactly the converse of that observed in salmon. As the salmon swims upstream to his spawning ground his muscles and other tissues atrophy and the arginine so liberated is used in the construction of new testicular tissue, the testes undergoing an enormous hypertrophy although the fish eats no food. The testicular atrophy in the rats on diets deficient in lysine, tryptophane and arginine was not the result of inanition, since the loss of weight in 3 of the 8 controls was as great or greater than that of the lysine- and argininedeficient ones, yet these 3 controls showed normal spermatogenesis while the amino-acid-deficient animals showed none. SUMMARY Observations are presented on the influence of a number of experimental dietary deficiencies on male factors in reproduction, and they show that there are a number of links in the nutritional chain necessary for the normal fertility of the male. Testicular atrophy is kno'wn to occur when food, generally speaking, is restricted, an effect which is perhaps due to deficient caloric intake and perhaps due to lack of specific dietary factors concerned with gonadal function. Testicular atrophy occurs with certain mineral deficiencies and with diets totally deficient in fat, conditions which probably never occur in the diets of human beings. Although limited damage may occur from some other avitaminoses, consistent testicular atrophy has been observed only in the rat and guinea pig with vitamin E deficiency. There is functional evidence that protein deficiencies, in particular, deficiencies of animal protein, impair testicular function. The amino acids arginine, tryptophan, and lysine are considered essential for normal spermatogenesis in the rat. Arginine deficiency in man was studied, and argenine was found essential for spermatogenesis.

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12 Vol. 11, No. 1, 1960 DJET AND FERTILITY MAKINo, H. Osaka Daigaku Igaku Zaschi 6:233, HIRAI, H., and TAKAGI, Y. Zool. Mag. (Tokyo) 64:301, EznANYAN, B. A. Izvest. Akad. Nauk Armyan. S.S.R., Biol. i Seikhoz. Nauki 7:73, New York University Post-Graduate Medical School Announces Post-Graduate Course in Gynecologic Endocrinology A practical, didactic and clinical presentation with emphasis on the therapeutic management of endocrine disorders in the female, including a discussion of the diagnosis and management of intersex will be offered. Endocrine therapy for menstrual abnormalities and ovulatory defects will be presented. Adrenocortical, thyroid, ovarian and pituitary abnormalities will be emphasized. Practical diagnostic tests are discussed and demonstrated, as well as the therapeutic use of the newer progestational, gonadal and corticoid steroids. Five-day, full-time course, April 18 through April 22, Tuition: $ Given under the direction of Dr. Herbert S. Kupperman. For further information, Office of the Associate Dean, New York University Post-Graduate Medical School, 550 First Avenue, New York 16, N.Y.