Biologic Background of Male Sterility

Transcription

1 Biologic Background of Male Sterility Carl R. Moore REPRODUCTION depends basically upon the interaction of a healthy male and female germ cell; hence male sterility may be conditioned during any phase of the life process that introduces conditions which will ultimately prevent the delivery of spermatozoa capable of fertilizing the egg. Three general life horizons may be involved, during any one of which conditions may develop that will render the male incapable of delivering spermatozoa in good condition. These may be designated as ( 1) the developmental period, leading to the establishment of a normal male system, ( 2) the prepuberal and puberal stage during which the functional capacity is attained, and ( 3) the period of sexual maturity when spermatozoa are produced and delivered for proper consumption. During the embryonic period the qualities inherent in the genetic male must be marshalled in proper sequence of developmental stages to bring into being the structural elements of the system, and the reproductive system, like other systems, is subject to the vagaries of embryonic development which may lead to atypical conditions. Each higher organism carries both male and female potentials and it has been shown experimentally, and from naturally-occurring incidents, that sexual differentiation is subject to different influences that may modify development in a normal sexuallydetermined individual. Hermaphrodites may occur, naturally or experimentally induced; an individual may fail to develop a testis; congenital absence From the Hull Zoological Laboratory, University of Chicago, Chicago, Illinois. Introduction to symposium on Male Infertility presented June 8, 1952, before the Eighth Annual Meeting of the American Society for the Study of Sterility, Chicago, Illinois, June 7, Personal researches have been aided by a grant from the Drs. Wallace C. and Clara A. Abbott Memorial Fund of the University of Chicago. 453 I '

2 454 MOORE [Fertility & Sterility of epididymis or vas deferens may occur, as may defective connections between testis and a proper outlet. The application of sex hormones during embryonic life may grossly modify development of the reproductive system, as do diets of the mother which are low in vitamin A. Abnormal phallic development may preclude later function. The basis of sterility, therefore, may rest upon a large number of different types of faulty embryology. Granted a normal development, the succeeding period of puberal development, during which the functional capacity of the system is gradually attained, is an important life period because of the establishment of those physiologic interrelationships with other functional systems which are necessary for proper activity in the reproductive system. Testicular descent occurs, without which sterility is assured. Spermatogenesis is developed gradually, as well as testis hormone secretion to provide necessary accessory functions. Proper adjustments with other endocrine glands (thyroid, pituitary) must be made before a functional capacity is assured. The prepuberal period is, therefore, of great importance for well-controlled function later. Thus, recognizing the opportunity for impedections to arise during these two early life phases, it is perhaps appropriate to devote the majority of our attention to the sexually mature period and to those conditions which may develop to render sterility a partial phenomenon or an absolute one. During the sexually mature stage structural abnormalities may arise which would preclude delivery of spermatozoa. Blocking of the outlet passages in the epididymis or vas deferens, or even the elimination of the testicle, may occur as a result of traumatic injury, venereal disease, or other maladies, or as a result of some type of surgery. Whereas these mechanical modifications are not infrequently the cause of sterility, physiologic influences on a br~ad pattern will receive primary consideration. Such physiologic influences may be grouped under general headings such as: ( 1) environmental influences; ( 2) nutritional factors; ( 3) hormonal aspects; ( 4) radiations; and ( 5) pathologies and general aspects. Environmental Influences The environment plays a marked role in the regulation of reproduction in the lower mammals. Just how much these may have application to human fertility has not been clearly delineated. The majority of mammals display a seasonal reproductive period during which the testes may be inactive, gametogenically or hormonally, for a large part of the year. The strictly

3 Vol. 3, No. 6, 1952] MALE STERILITY 455 controlled breeding season is followed by gonadal involutions, and the factors which regulate this are of both an internal and an external nature. The relation between the time span of night and day are highly important for some species of mammals, and for birds in particular. Thus with seasonalbreeding male birds the addition of daily increments of light, by artificial illumination, during late fall and winter have been instrumental in producing a testis with as full spermatogenetic activity as occurs normally during the spring breeding period Domesticated farm mammals such as the ram, although producing spermatozoa throughout the year, have been found to vary in sperm production during the different seasons. High temperatures exert an influence on spermatogenesis. The need for scrotal function to provide lower temperatures around the testicle in order that spermatogenesis may continue was pointed out in Testes of experimental animals are markedly injured or rendered totally aspermatic by applications to the scrotum of single treatments of water 7 C. above body temperature, by electric hot plate exposure, diathermy, prevention of heat loss from the body by masking of scrotal function, and other forms of exposure to higher temperatures. Exceptionally high summer temperatures have been held to be the cause of widespread sterility of bulls and rams. In Australia, rams maintained at ordinary summer temperatures at the seacoast showed a lack of spermatozoa at the same time that others, maintained in cooled sheds, had quantities of germ cells. That high temperatures likewise affect human spermatogenesis is attested to by the degenerate condition in the cryptorchid testis, the temporary or permanent sterility following prolonged febrile states (typhoid, influenza)/ 7 and the reduction in sperm count in normal men subjected to hyperpyrexia or artificial fever. 12 Nutritional Factors Nutritional factors may include inadequate intake of food as well as the specific absence of necessary constituents, among which may be vitamins and some amino acids and mineral salts. Thus, vitamin E has been found necessary for the production of spermatozoa; spermatogenetic tissues degenerate in the absence of small quantities of this substance. 16 Low vitamin B intake is accompanied by loss of sexual interest and gametogenetic involution, but since excessive B, along with a low intake of total nourishment, does not lead to improvement, the site of damage has been found to be the pituitary gland and not the testis. Inanition alone reduces the secretory

4 456 MOORE [Fertility & Sterility output of the pituitary and thus indirectly reduces testicular activity. 22 Low vitamin A leads to poor semen quality and gross effects upon the testes. 27 Absence of phenylalanine, one of the 10 essential amino acids, has been shown to cause serious deterioration of the gonads and accessory reproductive organs, presumably because of an effect upon the pituitary gland. Hormonal Aspects Sterility may depend upon abnormal hormonal relationships. It is now well-known that spermatogenesis in experimental animals requires the active secretion of a gonad-stimulating substance by the anterior lobe of the pituitary gland. Ablation of the pituitary leads to immediate retrogression of both gametogenetic and hormonal activities by the testis. Seasonalreproducing mammals show testis involution with diminished gonadotrophic activity in the pituitary. The inference is strong that a disordered pituitary function in man may reduce or abolish spermatogenesis. Thyroid secretions play a role, and thyroidectomy in cocks 2 or thiouracil treatments, which negate the action of the thyroid in rams or rabbits/ 5 results in the failure to produce germ cells or reduces the quality of semen in relative proportion to the amount of thyroid hormone available. Some indications exist that thyroxin may serve to stimulate spermatogenesis precociously in normal young. Estrogenic treatment of young or adult males prohibits spermatogenesis and hormone secretion by the testis, presumably through a reduction of secretions by the pituitary gland. Androgenic treatments of young males likewise lead to severe damage to the testis and spermatogenesis by virtue of reduced pituitary activity, but it was pointed out that a diminished effectiveness occurred as sexual maturity was reached, and also a diminished effect from androgens with an increased daily dosage. 21 'I'hese peculiar responses and other unexplained discrepancies relative to the effects of androgens on the testis "... leaves one searching for an apparently acceptable hypothesis that will bring the various findings into a common explanation." 21 Later work has shown that testis degeneration after hypophysectomy is prevented by treatments with androgens, but in general such treatments after testis degeneration has occurred seldom restore spermatogenetic function. In the wild seasonal-breeding ground squirrel it has been shown that androgens administered during the inactive period of spermatogenesis lead to sperm production. 30 Heckel,7 8 9 on the

5 Vol. 3, No. 6, 1952] MALE STERILITY 457 other hand, has consistently found that androgens administered to human patients lead to the elimination of sperm from the ejaculate. These problems still require valid explanations, since a similar protective action against hypophysectomy involution has been exerted by progesterone and yeast extract. To invoke a gonadotrophic function of androgens in such cases fails to clarify the underlying factors that are operative. Radiation Sterility is readily induced by irradiation, as was classically shown in the case of early workers with roentgen rays, and confirmed by repetition on experimental animals. It has been made clear that external radiation with x-rays, alpha, beta, and gamma rays, as well as neutrons, produce qualitatively the same type of testis degeneration. Similar degenerative effects in the testis have also been shown to follow internal administration of radioactive isotopes. 10 Pathologies and General Aspects Under the heading of pathologies or general influences many causes for sterility could be introduced. Functional adequacy of the accessory reproductive organs may play a role in the character of the sperm ejaculated. Spermatozoa leaving the testis are morphologically normal, but physiologically immature. 31 Capacityfor motility and fertility are acquired by spermatozoa during their passage through the epididymis-a period estimated on the basis of experiments as 14 to 18 days in the guinea pig and 11 days in the ram Spermatozoa not only undergo a physiologic maturation while passing through the epididymis, but also their life persistence and welfare is influenced through the epididymis by virtue of some action of testis hormone. In the epididymis of a guinea pig surgically isolated from the testis, or closed off to further sperm entry through ligation, spermatozoa retain their capacity to show motility when suspended in isotonic saline solution over a period of 2 months, provided that one testis is present to secrete hormone; when both testes are removed and no exogenous hormone is available, their capacity to demonstrate motility persists for less than 1 month. 19 Testis hormone likewise exerts an influence on spermatozoa through the character of the seminal secretions. Fructose and citric acid are secreted by the seminal vesicle and prostate gland under the influence of testis hormone,

6 458 MOORE [Fertility & Sterility and fructose is metabolized by spermatozoa, while citric acid is believed to play a role in the activation of motilityy 14 Low concentrations of fructose are associated with low grades of motility and fertility. Morphologically defective spermatozoa present in high proportions in the ejaculate are often associated with a low grade of fertility, and assessment of fertility potential is frequently based upon the morphologic character of the spermatozoa. Such atypical forms of spermatozoa appear to depend upon qualitative weakness in gametogenetic function, since rams ordinarily showing small numbers of defective sperm will quickly show an increase in atypical cells when the normal cooling function of the scrotum is prevented by insulating coverings. The curve, from low numbers of atypical sperm in the normal animal, rises to a peak as scrotal function wanes to a point where no germ cells are produced; but when the insulating scrotal coverings are removed, normal spermatozoa reappear in the ejaculate with -for short periods at least-an almost complete absence of atypical forms. 23 The phenomenon of recovery from injury constitutes reactions to many harmful conditions. Injury from heat exposure, inflammatory conditions, restoration of proper nutrient intake, and even irradiation injury may be followed by good spermatogenetic recovery, provided the injury has not been too severe. An exception appears to reside in the sterility resulting from lack of vitamin E, since it appears that sterility from such a cause is permanent and not subject to reversal.. Local or general testicular injuries often occur without reference to a specific cause. Seminiferous tubule activities in producing spermatozoa frequently suggest a delicate mechanism, and, without doubt, one influenced by disordered metabolic conditions not now understood. Thus Sand and Okkels 26 collected well-preserved testicles from cases of sudden death by accident or suicide, or from cases not associated with long illness or obvious general pathology. Among 65 cases obtained from ages 30 to 40 years, only 17, or 24 per cent, approached the normal type of testis. Edematous interstitial areas, thickened capsule; of the tubule, fibrosis, hyalinization, cytolysis, and other conditions doubtless represented a register of unknown, unfavorable conditions. Finally, a factor of heredity may be present that is none too easily expressed with definiteness. Gradational strengths of masculinity is a wellknown concept; and qualitative breeding strength within different breeds is

7 Vol. 3, No. 6, 1952] MALE STERILITY 459 not uncommon to the stock breeder. Sufficiently wide crosses between species, such as the horse and ass, yield hybrid forms (the mule) which, although developing a testicle that is able to carry on spermatogenesis to partial completion, is yet unable to produce mature germ cells. Thus the opportunities to develop sterility in the male are legion and may depend upon definite morphologic blocks, deranged functional operating mechanisms, faulty nutritional conditions, or extraneous environmental causes. Senility, per se, is probably not a factor, whatever senility may be. Well-documented observations on human testes between the eightieth and ninetieth year reveal continuous spermatogenesis. Whereas such testicles may not be carrying on an intensity of function characteristic of youth, one may enquire what organ system does? REFERENCES 1. BENOIT, J. Facteurs externes et internes de l'activite sexuelle. I. Stimulation par la lumiere de l'activite sexuelle chez Canard et la Cane domestiques. Bull. biol. France-Belg. 70:487, BLIVAISS, B. B. Interrelations of thyroid and gonad in the development of plumage and other characters in brown Leghorn roosters. Physiol. Zool. 20:67, DvosKIN, S. Local maintenance of spermatogenesis by intratesticularly implanted pellets of testosterone in hypophysectomized rats. Am.]. Anat. 75:289, DvosKIN, S. The effect of pregnenolone on reinitiation of spermatogenesis in hypophysectomized rats. Edocrinology 45:370, GuNN, R. M. C. Fertility in sheep. Artificial production of seminal ejaculation and the character of the spermatozoa contained therein. Commonwealth of Australia. Council for Sci. and Indust. Res. Bull. #94, GuNN, R. M. C., and SANDERS, R. N. 2. Seasonal changes affecting fertility in rams. Commonwealth of Australia. Council for Sc. and Indust. Res. Bull. # 148, HECKEL, N. J. Production of oligospermia in a man by use of testosterone propionate. Proc. Soc. Exper. Biol. & Med. 40:658, HECKEL, N. J. The influence of testosterone propionate upon benign prostatic hypertrophy and spermatogenesis. A clinical and pathological study in the human. ]. Urol. 43:286, HECKEL, N. J. The rebound phenomenon of the spermatogenetic activity of the human testis following administration of testosterone propionate. Fertil. & Steril. 3:49, HELLER, M. "The Testis." In BLOOM, W. (ed.): Histopathology of Irradiation from External and Internal Sources. New York, McGraw-Hill, LUDWIG, DoRoTHY J. The effect of androgens on spermatogenesis. Endocrinology 46:453, MACLEOD, J., and HoTCHKISS, R. S. The effect of hyperpyrexia upon spermatozoa count in man. Endocrinology 28:780, MANN, T. "Metabolism of semen." In Advances in Enzymology. New York, Interscience, p. 329, 1949.

8 460 MOORE [Fertility & Sterility 14. MANN, T., and LUTWAK-MANN, C. Secretory function of male accessory organs of reproduction in mammalia. Physiol. Rev. 31:21, MAQSOOD, M. Influence of thyroid status on spermatogenesis. Science 114:693, MAsoN, K. E. "Relation of the vitamines to the sex glands." Sex and Internal Secretions (ed. 2). Baltimore, Williams and Wilkins, MILLS, R. G. The pathological changes in the testes in epidemic pneumonia. ]. Exper. Med..90:505, MooRE, C. R. The biology of the mammalian testis and scrotum. Quart. Rev. Biol. 1:4, MooRE, C. R. Spermatozoon activity and the testis hormone. ]. Exper. Zool. 50:455, MooRE, C. R. "Biology of the testis." Sex and Internal Secretions (ed. 2). Baltimore, Williams and Wilkins Co., MooRE, C. R., and PrucE, DoROTHY Some effects of testosterone and testosterone propionate in the rat. Anat. Rec. 71:59, MooRE, C. R., and SAMUELS, L. T. The action of testis hormone in correcting changes induced in the rat prostate and seminal vesicles by vitamine B deficiency or partial inanition. Am. f. Physiol. 96:218, PHILLIPS, R. W., and McKENzm, F. F. The thermo-regulatory function and mechanism of the scrotum. Res. Bull Missouri Agric. Exp. Sta., RowAN, W. Experiments in bird migration. I. Manipulation of the reproductive cycle: seasonal histological changes in the gonads. Proc. Boston Soc. Nat. History 39:151, RowAN, W. Light and seasonal reproduction in animals. Biol. Rev. 13:314, SAND, K., and 0KKELS, H. The histological variability of the testis from normal and sexual-abnormal castrated men. Endokrinologie 19:369, SAPSFORD, C. S. Seasonal changes in spermatogenesis in rams: their relation to plane of nutrition and to vitamine A status. Australian Jour. Agric. Res. 2:331, SIMEONE, F. A. A neuromuscular mechanism in the ductus epididymis and its impairment by sympathetic denervation. Am. /. Physiol. 103:581, TooTHILL, M. A., and YouNG, W. C. The time consumed by spermatozoa in passing through the ductus epididymis of the guinea pig as determined by means of India ink injections. Anat. Rec. 50:95, WELLS, L. J., and MooRE, C. R. Hormonal stimulation of spermatogenesis in the testis of the ground squirrel. Anat. Rec. 66:181, YouNG, W. C. A study of the function of the epididymis. I. Is the attainment of full spermatozoon maturity attributable to some specific action of the epididymal secretion? ]. Morph. & Physiol. 47:419, YouNG, W. C. III. Functional changes undergone by spermatozoa during their passage throug-h the epididymis and vas deferens in the guinea pig. Brit. ]. Exper. Biol. 8:151, 1931.