Relation of the Endocrine Glands to Senescence
As the metabolic activities of the cells of the body generally are markedly influenced by the secretions of the ductless glands, the relations between these endocrine glands and senescence demand some discussion.
The process of reproduction leads to rejuvenescence in the protozoa, and it might therefore be imagined that in the higher animals continued activity of the sexual glands would similarly exert a rejuvenating influence on the remaining cells of the body. But the process of specialization has gone so far in the cells of the higher animals that the highly differentiated cells, especially of the nervous system, cannot fairly be compared with the constituent molecules of a unicellular organism. As sexual activity is the biological reason for existence and as in vigorous men sexual power may last long beyond the usual period, man being regarded as old as his sexual glands, it has been widely imagined that the functional activity of the sex glands is in some way a cause, rather than a manifestation, of the preservation of bodily vigour, and conversely that failure and atrophy of the sexual glands cause old age and senility. There is an attraction, though not without the danger of fallacies, in interpreting the words of older writers as prophetic anticipations of quite modern knowledge. But with this caution in mind there is some ground for crediting Hufeland[93] with some idea of the internal secretion of the sexual glands: as long ago as the end of the eighteenth century he wrote “the organs of generation have the power of secreting the finest and most spiritual parts of our nourishment; but at the same time they are so organised that these perfected and ennobled juices can again return and be received into the blood. Like the brain, therefore, they belong to those important organs which serve for bringing to perfection and ennobling our organic matter and power, and even ourselves.”
Since 1889 when Brown-Séquard, at the age of 72 (6 years before his death) put forward the idea that rejuvenation could be brought about by the hypodermic injection of testicular emulsion, the view that old age and senile changes are due to failure of the glands of internal secretion has become popular. The thyroid (V. Horsley, Léopold-Lévi), the testis and ovary, or most or all of the glands (pluriglandular insufficiency) have been incriminated; Lorand,[94] indeed, regards old age as a disease caused by degeneration of not one but several of the endocrine glands, Biedl[95] expresses much the same view in referring old age to a disturbance of the endocrine balance, and Berman[96] in a recent semi-popular book states that old age is an exhaustion permanent and irreparable of all the glands of internal secretion; like Lorand he ascribes considerable importance to failure of the internal secretions of the sexual glands. It is highly desirable to arrive at some conclusion as to the relation between changes in the glands of internal secretion and senescence, for in medical practice this conception of cause and effect has been acted upon; various glandular extracts have been employed to counteract and delay the disabilities that may accompany advancing years and, though not so freely, operations, viz., ligature of the vas deferens and implantation of testicular grafts, have been carried out.
Lydston[97] implanted testes from boys recently dead into men with atrophied or destroyed testes and reported improvement. Stanley and Kelker[98] implanted 11 cases with testicular grafts obtained from executed criminals, and 5 cases with the testes of rams, obtaining improved general condition, though not claiming that life was prolonged. Stanley[99] injected by means of a large syringe strips of testes of rams, goats, or bears under the skin of the abdomen of more than 300 prisoners, and stated that conditions of neurasthenia and senility were relieved.
The stimulating effect of thyroid secretion on growth and metabolism, shown both experimentally and clinically in the therapeutic triumphs of thyroid treatment in myxoedema and hypothyroidism, seems to justify the view that failure of thyroid function plays an important part in reducing the capacity for multiplication and regeneration of cells. Between the manifestations of hypothyroidism and those of old age there are undoubtedly striking resemblances, such as the dry skin, the loss of hair, the diminished mental and bodily energy, and the increased amount of interstitial fibrous tissue. In some respects myxoedema and cretinism imitate the senile state; myxoedema has indeed been described as more than a simulation and as the best example of secondary senilism (Hastings Gilford[100]); but this is a very different condition from healthy old age which does not present the picture of complete loss of thyroid function; old age therefore cannot be regarded as due to athyroidism. Usually atrophy of the thyroid accompanies and corresponds to that of the senescent body as a whole. No doubt pathological changes may occur in the thyroid, especially in women, during advancing years, and it is in such instances that thyroid feeding produces so much improvement that it has revived in our day the hope of an elixir of life and perpetual youth. It is not improbable that the administration of thyroid gland extract may, by preventing high blood pressure, delay or obviate the onset of arteriosclerosis, and so stave off senility due to this cause, but this is pathological old age and not the physiological involution.
In addition to the seminal tubules and ova, which provide their external secretion, the testes and ovaries contain the interstitial cells described by Bouin and Ancel[101] or, in Steinach’s phrase, “the puberty gland”; the germ cells and the interstitial cells differ from each other in structure, function, and reaction to external influences; thus the germ cells though dominant are more susceptible to damage, for example by ligature of the vas deferens, x-rays, alcoholism, or pressure, as in the case of a cryptorchid. It is stated that when the seminal tubules are active and prominent the interstitial cells are scanty, and conversely that when the seminal tubules atrophy the interstitial cells multiply; Lipschülz, Ottow, Wagner, and Bormann[102] showed that hypertrophy of the interstitial cells as observed in various experimental conditions depends on local factors in the testes and has nothing to do with their internal secretion in relation to the body as a whole. After ligature of the vas deferens in animals there are, according to Steinach, Kuntz,[103] and others, two stages (1) the seminal tubules atrophy while the interstitial cells multiply, and (2) after some time the seminal tubules regenerate while a certain amount of increase in the interstitial cells persists. Nathan[104] ascribes the regeneration of the seminal tubes to the influence of the interstitial cells, which he considers act like young connective tissue by favouring growth. The interstitial cells of Leydig in the testis and the interstitial or lutein cells of the ovary are generally regarded as responsible by their lipoid internal secretion or hormone for the secondary sex characteristics (Bouin and Ancel, K. Sand[105]), though Blair Bell[106] and Sternberg[107] deny this. Sir Frederick Mott,[108] who has extensively investigated the interstitial cells, especially in connexion with dementia praecox and other forms of mental degeneration, concludes that in fetal life they act as sex determinants, and that later in life they are responsible for the sexual appetite. It has been argued that atrophy of the interstitial cells is the cause of senescence. Against this view is Sir Frederick Mott’s observation that after birth the interstitial cells undergo progressive atrophy and disappear, that they reappear and are in a state of functional activity at puberty (a sequence of events described by Aron[109] as two different interstitial glands), and that they are present in extreme old age; Retterer[110] also described their presence in the testes of men over 70 years of age. So far it might be concluded that changes in old age, such as diminution in number and pigmentation, shown by the interstitial cells, are not the cause but an accompaniment of senescence.
Kenneth Walker’s[111] observation that the interstitial cells of the testis show a gradual diminution in number from the age of about 30 years, might be quoted in favour of the contention that atrophy of these cells plays a part in the production of senescence. In addition there are the dramatic experiments on rats carried out by Eugen Steinach,[112] who was formerly Professor of Physiology in the German University of Prague and since 1912 has been Director of the Physiological Section of the Experimental Biological Institute at Vienna. He found that in apathetic senile rats with degenerative changes in the thyroid, pituitary, and interstitial cells ligature or section of one vas deferens causes atrophy of the seminal tubes and active growth of the interstitial cells; the hormone thus provided stimulates the thyroid, pituitary, and brain, and the rat is rejuvenated, the sexual instincts and emotions become active, and the rat may have offspring; when relapse into senility occurs, a repetition of the operation on the other side brings about a further rejuvenation; and later the same result is effected by grafting the testes of a young rat. In this way life is definitely prolonged. This procedure has been advocated in man with some success by Steinach; Lichtenstern of Vienna, who has done 36 such operations and 21 implantations on account of senile changes, has not encountered any bad results, but admits that he has not been uniformly successful, and that the number of cases is not sufficient to justify a final conclusion. From observation in Vienna Benjamin[113] estimated that the operation was followed by no results at all in from 10 to 20 per cent of the cases. Obviously a considerable time must elapse before any decision as to prolongation of life can thus be assured.
In the autumn of 1921 a man aged 70 was advertised to speak at the Albert Hall on “How I was made 20 years younger by the Method of Dr. Steinach of Vienna,” but he died on the morning of the day from pneumonia (Benjamin[113]), the necropsy not revealing, so it is said, any trace of an operation; the hypertrophy of the interstitial cells, however, may have been induced by the exposure of the testes to x-rays.
Steinach’s observations naturally aroused great interest and have been repeated with discordant results by a number of investigators: Simmonds[114] and Tiedje[115] have failed to confirm the occurrence of the changes in the testes after vasectomy; and Romeis[116] and Marinesco[117] have not obtained the striking clinical results described by Steinach. Levy Lenz and Schmidt,[118] however, report rejuvenation in 23 out of 24 cases of vasectomy, and Voronoff encouraging results from implantation of chimpanzee’s testes into man. But Marinesco compares Steinach’s published results with those of Brown-Séquard.
It may be added that the operation of ligature of the vas deferens which was performed some 25 years ago, before prostatectomy became established, in order to cause atrophy of enlarged prostate, was not noticed to be followed by rejuvenescence. Mr. C. Mansell-Moullin, who published[119] a series of 14 such cases, has kindly informed me that his patients did not show any evidence of such a change. Romeis has also raised this objection to Steinach’s results which it has been thought might be explained by suggestion (Freudenberg)—a view hardly tenable in the light of the remarkable results described in animal experiments.
The internal secretion of the ovary has never been isolated, and the evidence of its existence rests on the results of removal. Castration in men and in women does not bring on the phenomena of old age, though this operation is followed by well-marked changes as regards the secondary sex-characters, and, according to Voronoff, eunuchs are short-lived. It may also be pointed out that the obesity so common after castration is not a feature of “the lean and slippered pantaloon.” Further, after the menopause the ovaries undergo fibrotic atrophy, and it appears from Professor Turnbull’s observations (vide p. 114) that the interstitial cells are very scanty or absent; further observations are necessary as to the presence of interstitial cells in senescent ovaries, but presuming that they are scanty it would follow, on the hypothesis that the interstitial cells exert an influence in preventing the onset of old age, that women should become old much sooner than men in whom the interstitial cells are apparently much more in evidence. It cannot of course be admitted that such a difference in the sex incidence of old age exists. The improved health and rejuvenation after x-ray treatment for metrorrhagia and uterine fibromyomas at the climacteric or post-climacteric age have been regarded by Steinach and Bordier as due to hypertrophy of the ovarian interstitial cells following induced atrophy of the ova, but to accept this there must be definite evidence that the interstitial cells are increased in number. Harrower’s[120] dictum that the absence of a hormone provided by the interstitial cells is responsible for premature senility does not appear to be borne out by our present knowledge, but a great deal of further work must be done before a final decision is justified.
Testicular and ovarian extracts, often in combination with those of the thyroid and pituitary, which are known to have a definite physiological action, have been extensively used as a panacea. But is there any undeniable evidence that the extracts of testis and ovary so far employed have any effect apart from that of suggestion? According to Frank[121] the available ovarian preparations are defatted and thus deficient in the potent lipoid extracts; and very serious doubts as to the activity of testicular extracts have been expressed by Professor Cushny.
The possibility must be borne in mind that the use of thyroid and other gland extracts that have a definite effect on metabolism is not devoid of risk to cells that are gradually undergoing involution; for, by stimulating metabolism unduly, the existing vitality may be prematurely exhausted and, though for a time there is a gratifying show of energy, it is but a flash in the pan that precedes a more rapid loss of function. We are irresistibly reminded that “no man putteth new wine into old bottles: else the new wine doth burst the bottles.”
At the present time it would be unwise to express a dogmatic opinion about the relation of the endocrine glands to normal old age. That old age is due to endocrine insufficiency or loss of balance cannot be regarded as proved, and it is probably safer to regard changes, such as atrophy, in the various glands of internal secretion as concomitant with, rather than causal of, those in the senescent body.