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Role of Thyroid on Maturity and Fertility in the Male
Role of Thyroid on Maturity and Fertility in the Male M. Maqsood, Ph.D.
CONSIDERABLE WORK has been done in the field of thyroid physiology, but further work is needed to elucidate the role of the thyrOid gland in the regulation of various reproductive processes in both sexes of animals. Previous workers, not realizing the importance of the thyroxin secretion rate as a basis for determining the effective dose, have administered either too little or too much thyroid material, and in consequence have reported quite contradictory results. IS In the past, factors such as breed and strain differences, sex and age of the animal, stage of sexual development, duration of the hormone administration, and seasonal variations in the environmental temperature, all of which appear to effect the thyroxin secretion rate, were not taken into consideration while studying the role of the thyroid gland in the field of reproductive physiology. Broadly speaking, the rate of secretion of thyroxin is the amount secreted into the general circulation in a given period of time under specified conditions. With the previous work in view, it was considered desirable to elucidate the role of the thyroid gland in the regulation of various male reproductive processes, and research work was carried out on the male mouse, rabbit, and ram, type species selected for the present investigation. The work reported was carried out at the Michigan State College and the University of Cambridge during the years 1948-1951.
From the Department of Physiology and Pharmacology, Michigan State College, and Animal Research Station, Cambridge University, England. The author is thankful to Dr. J. Hammond, Dr. A. Walton, and Dr. T. Mann, of the University of Cambridge, England; Professor E. P. Reineke of the Michigan State College, and Dr. S. J. Folley, of the University of Reading, England, for their help and encouragement during the course of the present work. 382
.
TABLE 1.
Effects of Continuous Thyroid Stimulation or Inhibition on Sexual Desire and Semen Qualities of Young Male Rabbit Age at Start of Experiment-4 Weeks. Treatment Period-40 Weeks
No. Group animals
Treatment
Libidoa
2.4 ± .07 2.6 ± .07 2.9 ± .OB 3.3 ± .OB
1
4
Control
2
4
0.004% TP
3
3
O.OOB%TP
3a
3
41 51
4 3
0.0080.004%TP O.l%TH Thyroidectomized
t
2.27 4.19 71 3.20U
Volume b mi·
0.59 ±.031 0.69 ±.031 0.73 ±.036 0.97 ±.036
t
2.BO
2.21' 7.56u
TP, Thyroprotein t value obtained by comparing group Nos. 2, 8, and 8a with group No. 1. a to 8 means of 15, 14, 6, 6 and 6 reading respectively. I Onset of sexual maturity was completely arrested. u Level of significance-O.l%. 71 Level of significance-l%. • Level of significance-5%.
Density" million
225 ± 13.3 252 ±13.3 331 ± 15.4 503 ± 15.4
Abnormal sperm 8 t
2.1B 3.1Bi 13.62U
Motilityd
%
2.5 ±.12 2.6 ±.12 3.0 ±.14 3.7 ±.14
27.6 ± 1.57 0.74 2.73 i
4.55 71
TH, Thiouracil
24.B
± 1.57 19.0 ± 1.B2 13.2 ± 1.B2
2.05 3.5771 5.97u
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THYROXIN DOSAGE AND STAGE OF SEXUAL DEVELOPMENT
Figure 1 shows that the effects of the administration of thyroprotein (iodinated casein containing 0.72 per cent L-thyroxin on bioassay) on the
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Fig. 1. The influence of variations in environmental temperature and thyroid status on the weight of the testes and seminal vesicles of young male mice. Thyroprotein (TP) and thiouracil (TU) were fed on percentage basis for a period of 4 weeks under different environmental temperatures as shown in each column. In Expts. I and II the seminal vesicles were weighed after gently squeezing out the seminal fluid, while in Expts. III and IV these were weighed intact with the seminal fluid.
weights of the testes and seminal vesicles of the young male mouse, kept at environmental temperatures of 24°C. and 30°C. for a period of four weeks, varied with the dose of the hormone administered. 3 Moreover, histologic examination of the testes and seminal vesicles of the experimental mice
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. showed that the administration of moderate doses of thyroid materials stimulated spermatogenic activity and caused epithelial proliferation of the mucosa of the seminal vesicles (with numerous secretion granules) when compared with those of the control groupS.21 The administration of larger doses of thyroid materials adversely affected the development of the testes 0
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and seminal vesicles of the treated mice. Keeping in view the significance of the thyroxin secretion rate in the present investigation, it was estimated in the male rabbit at 4, 8, 16, 32, and 48 weeks of age by the thyroxin-thiouracil technic. 7 The thyroxin secretion rate increased with advancing age, but showed a decrease when calculated per 100 Gm. body weight in the growing male rabbit as shown in Fig. 2.
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DURATION OF THYROXIN ADMINISTRATION
In view of these findings, it was decided to find out whether a constant dose of thyroxin should be administered throughout the growth period, or whether the dosage levels should be increased or decreased in accordance with the rate of secretion of thyroxin in order to produce precocious sexual maturity. Taking into consideration the estimated thyroxin secretion rate at
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different age periods as the fundamental basis, the optimal doses of thyroxin which would stimulate the reproductive processes in the growing male rabbit at different ages were determined by the simultaneous administration of graded doses of thyroxin and thiouracil for short or long periods under natural environmental conditions. The effects of these treatments on the TABLE 2.
Effects of Continuous Thyroid Stimulation or Inhibition on Weights of Testes and Accessory Organs of Young Male Rabbit Age at Start of Experiment-4 Weeks. Treatment Period-40 Weeks Testes
4
2
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3"
3
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4
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5
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Weight
Weight
No.
Group animals
I
Seminal Vesicles
Treatment
(mg.)
tb
Control
5839 ± 31.4 0.004%TP 5882 ± 31.4 O.OOB%TP 5863 ± 36.2 7348 0.0080.004%TP ±36.2 O.I%TH 3024 ± 31.4 Thyroid2931 ectomized ± 36.2 TP, Thyroprotein
0.61 0.54 31.470 63.42 0 60.65 0
(mg.)
Prostate Weight
tb
(mg.)
tb
736 81B ±9.7 ±8.9 748 0.32 853 1.B2 ±B.9 ±9.7 764 1.89 859 2.10 ± 11.2 ± 10.2 898 10.960 876 4.254 ± 10.2 ± 11.2 412 22.6 0 548 21.50 tl ± 9.7 ± 8.9 442 10.B9 o 567 18.50 ± 11.2 ± 10.2 TH, Thiouracil
"Group S was fed with thyroprotein as 0.008 per cent of the ration from fourth to twentieth week and then divided into two subgroups. Subgroup 3 was continued on the same level of thyroprotein while subgroup Sa was fed with thyroprotein as 0.006 per cent of the ration till the thirty-sixth week, when the dose was further reduced to 0.004 per cent which was continued till the end of the experiment. b t value obtained by comparing groups 2 to 5 with group l. o Level of significance-O.l%. tl Level of significance-l%. 6 Level of significance-5%.
weights of the male sex organs, on the process of spermatogenesis, development of the interstitial cells, age of sexual maturity, libido, and semen qualities in the rabbit and the Suffolk sheep were determined. Continuous administration of thyroxin within the optimal phYSiologic limit resulted in precocious sexual maturity of the treated rabbits when compared with those of the control groups6, 11, 14 (Tables 1 and 2). The testes of the treated rabbits showed active spermatogenesis, and the interstitial cells appeared well developed and more numerous than those of the control or thiouracil-treated groups (Figs. 7 and 9). The epithelial cells lining the walls of the epididymal ducts appeared well developed, and
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the lumina contained masses of spermatozoa (Figs. 8 and 10). The administration of thyroxin in large doses adversely affected the development and functions of the male sex organs in the young rabbits, while its administration in doses below or about equal to the estimated thyroxin secretion rate
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Fig. 3. Graphic representation of the data on libido and semen qualities of the control and thyroprotein-treated inbred rabbits. The administration of thyroprotein (TP) as 0.008-0.004 per cent of the ration was started at the age of 4 weeks and continued till the age of 44 weeks. Thyroid therapy resulted in precocious sexual development and improved the libido and semen qualities of the treated rabbits when compared with those of the control group. Libido and sperm motility are expressed in estimated score values.
had no effect on the various male reproductive processes. Moreover, it was observed that the continuous administration of a constant dose of thyroxin throughout the growth period was without any beneficial effect on the various male reproductive processes in the rabbit. The reason for this is that the thyroxin secretion rate increases with age,
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Fig. 4. Graphic representation of the data on libido and semen qualities of the control and thyroprotein-treated young Suffolk rams during the breeding and nonbreeding seasons (1949-50). Thyroprotein treatment resulted in precocious sexual maturity, considerably improved the libido and semen qualities, and prevented the seasonal decline in male fertility during the nonbreeding season when compared with those of the control group. Semen samples were collected twice a week throughout the year by means of artificial vagina. Libido and sperm motility are represented in the estimated score values and the age at the time of first ejaculate was taken as the age of onset of sexual maturity. The hours of daylight from September to August were calculated from the Nautical Almanac, 1949, for latitude 52° N (the approximate latitude of Cambridge). The mean atmospheric temperature was calculated from the daily maximum and minimum temperatures.
Fig. 5. Testis section of an 8-week-old thyroxin-treated inbred buck rabbit (experimental period 4 weeks) showing increased spermatogenic activity when compared with the controls. A number of the seminiferous tubules show cavity formation (hematoxylin and eosin stain). (X 280) Fig. 6. Testis section of an 8-week-old thiouracil-treated rabbit (experimental period 4 weeks) showing arrested spermatogenic activity when compared with the controls or thyroxin-treated ones (Fig. 7). The tubules are not yet canalized. (X 280) Fig. 7. Testis section of a 20-week-old thyroxintreated rabbit (experimental period 16 weeks), showing all stages of spermatogenesis. Note the maturing spermia attached to the Sertoli cells. (x 280)
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and its level does not remain constant throughout the growth period in the rabbit (Fig. 2). Thyroxin, when administered within the optimal physiologic limits to 4, 12, 28, and 44-week-old rabbits for a period of 4 weeks, stimulated the various male reproductive processes when compared with those of the control or thiouracil-treated groups (Figs. 5, 6, 11 and 12).n In long term experiments, the administration of thyroxin in optimal physiologic doses, corresponding to the thyroxin secretion rate at different age periods in the rabbit, considerably improved the libido and semen quality when compared with those of the control groups (Fig. 3). The continuous administration of thyroprotein within the physiologic limits resulted in precocious sexual maturity in the Suffolk sheep, and there was considerable improvement in the libido and semen quality throughout the year when compared with those of the control group (Fig. 4). The thyroprotein-treated animals showed the onset of sexual maturity at an average age of 20.3 -f- 0.54 weeks, and the control ones at an average age of 29.0 -f- 0.67 weeks. The difference in the age of onset of sexual maturity (the age at which the first ejaculate was collected) was statistically significant (t = 10.10). EFFECTS OF THIOURACIL ADMINISTRATION The feeding of thiouracil (2-thio-6-oxypyrimidine) as 0.1 per cent of the ration to the young male mouse and rabbit at different age groups for short periods resulted in a significant decrease in the weights of the male sex organs. 1l • 21 On histologic examination, the testes showed arrested spermatogenic activity and some atrophic and degenerative changes (Fig. 9). The epididymal ducts of the thiouracil-treated rabbits were poorly developed and contained some degenerated spermatogenic cells (Fig. 10). Some degree of desquamation and inactivity of the epithelial cells lining the Fig. 8. Epididymis section of a 20-week-old thyroxin-treated rabbit (same as in Fig. 9), showing a mass of sperm in the cavity. The epithelial cells lining the ducts Fig. 9. Testis show an increase in cell height (compare with Fig. 10). (X 280) section of a 20-week-old thiouracil-treated rabbit (experimental period 16 weeks) showing arrested process of spermatogenesis. The spermatogenic cells show atrophic and degenerative changes. Some of the sloughed off cells are seen free in the lumina of tubules. (X 280) Fig. 10. Epididymis section of a 20-week-old thiouraciltreated male rabbit (same as in Fig. 9), showing the presence of degenerated spermatogenic cells in the ducts. The epithelial cells lining the ducts show a decrease in cell height. (X 280)
Fig. 11. Testis section of a 32-week-old thiouracil-treated rabbit (experimental period 4 weeks) showing some degree of arrested spermatogenic activity in the seminiferous tubules. The cavities of the tubules contain protoplasmic debris. (X 280) Fig. 12. Testis section of a 32-week-old thyroxin-treated rabbit (experimental period 4 weeks) showing increased spermatogenic activity when compared with the control ones. The maturing spermia appear to be better developed (compare with Fig. 11). (X 280) Fig. 13. Testis section of a young SuHolk ram during the breeding season showing the degree of spermatogenic activity (compare with Fig. 16).
,
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mucosa of the seminal vesicles of the mouse was also observed. Accumulation of these desquamated cells in the seminal fluid was seen in the lumina of the seminal vesicles. 21 Prolonged thiouracil treatment or thyroidectomy in the young male rabbit and sheep arrested the onset of sexual maturity, and the treated animals neither showed any libido nor produced any ejaculateY Lack of sexual desire and arrested growth of the accessory male sex organs of the treated animals also indicated interference with the production of the male sex hormone by the interstitial cells, which showed a considerable decrease in number. The degree of impairment of the various male reproductive processes varied with the age of the animal, and with dose and duration of the treatment period. Figure 16 shows the effects of the administration of thiouracil on the histology of the testis of the ram for a period of about 12 monthsY Histologic studies of the testes of the thiouracil-treated rams indicate that the degree of impairment of the normal process of spermatogenesis becomes more and more pronounced with the prolongation of the treatment period. The adverse effects of thiouracil treatment or thyrOidectomy were more marked in the younger animals than the older ones because the demand for thyroxin for the development of the various physiologic processes is. comparatively higher in the younger animals. It was interesting to find that the administration of thyroxin, in amounts about equal to the estimated thyroxin secretion rate in the growing male rabbit simultaneously fed with 0.1 per cent thiouracil as part of the ration, maintained the male reproductive processes up to those of the control groups. The results obtained demonstrated rather clearly that the level of thyroxin (x 280) Fig. 14. Testis section of a 16-month-old control ram (during the nonbreeding season) showing arrested spermatogenesis, with some maturing spermia attached to the Sertoli cells, in some of the seminiferous tubules. The interstitial cells show a comparative decrease in number. (x 280) Fig. 15. Testis section of a 16-month-old thyroxin-treated ram (during nonbreeding season) showing active spermatogenesis in majority of the tubules. Note a large mass of maturing spermia in the tubules. The interstitial cells appear well developed (compare with Figs. 13 and 14). (X 280) Fig. 16. Testis section of a 16-month-old thiouracil-treated Suffolk ram (after 12 months of thiouracil treatment). Note the spermatogenic cells are sloughed off in practically all of the seminiferous tubules and the tubules contain a syncytium of Sertoli cells. The tubules have greatly decreased in diameter. Some remains of the degenerated spermatogenic cells are still seen in some of the tubules. (x 280)
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in the blood has a pronounced influence on the development and functions of the male sex organs in the growing animals. This is because the administration of thyroxin in amounts below or about equal to the estimated thyroxin secretion rate in the growing animals was ineffective, since such amounts of exogenous thyroxin simply depressed the production of the thyrotrophic hormone, with the result that the endogenous thyroxin level was reduced by an amount equivalent to the exogenous thyroxin administered. In such cases, the final level of thyroxin in the blood remained the same. Moreover, any intederence with the normal production of the thyroid hormone by the thyroid gland, such as administration of thiouracil or thyroidectomy, adversely affected the various male reproductive processes in young animals.
EFFECT OF SEASONAL VARIATIONS The experimental data indicated that during the period of seasonal decline in male fertility, the so-called "summer sterility" in the ram, there occurs a decrease in the thyroxin secretion rate since the continuous administration of thyroxin in optimal physiologic doses throughout the year practically maintained the male reproductive processes during the nonbreeding season to those levels observed during the breeding season (Fig. 4),11 This evidence was obtained by evaluating the libido and semen qualities, and by histologic examination of the testes of the treated and control rams during the breeding and nonbreeding seasons. During the non breeding season, the testes of the Suffolk ram in Cambridge, England, showed limited spermatogenesis and a decrease in the number of the interstitial cells, while the testes of the thyroxin-treated rams showed active spermatogenesis, and the interstitial cells were numerous and well developed (Figs. 14 and 15) Y The so-called "summer sterility" in the ram which occurs during the summer months in the United States is due to high environmental temperature. 1 , 22 An increase of only 6°C. from 24°C. to SO°C. in the environmental temperature resulted in atrophic and degenerated changes in the testes and seminal vesicles of the young male mouse. 21 Moreover, the length of daylight does not appear to affect the weight, histology, and functions of the male sex organs in the rabbit (inbred strains) at different age periods. 19 During the summer months, the rate of secretion of thyroxin declines Significantly below the winter value in the young male rabbit, and it was interesting to find that during this period there occurred a decline in male fertility,11 It was observed that the administration of thyroxin within the optimal physio-
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THYROID AND MALE FERTILITY
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logic limits considerably improved the various male reproductive processes in the young male rabbit during the summer months. Thyroxin therapy also improved the libido and fertility rate in a young Essex boar (inbred) which
Fig. 17. Stained semen smear from a so-classed subfertile buck rabbit, showing tailless sperm. (x 1300) Fig. 18. Stained semen smear from a previously subfertile buck rabbit after thyroid therapy. Note a marked decrease in the number of abnormal sperm (compare with Fig. 17). (X 1100) Fig. 19. Testis section of a subfertile buck rabbit, showing arrested spermatogenesis and the presence of a few giant cells. Note a marked decrease in the number of interstitial cells. (X 280) Fig. 20. Testis section of a subfertile buck rabbit after thyroid therapy showing a marked improvement in the process of spermatogenesis. The tubules contain numerous maturing spermia (compare with Fig. 19). (X 280)
before the start of the treatment showed very poor libido and a decline in fertility during the summer.1S These studies indicate that high environmental temperature adversely affects the male reproductive processes in some species of animals, and that
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MAQSOOD
the thyroid gland may be the physiologic medium through which seasona] variations affect the male reproductive processes. EFFECT OF AGE VARIATIONS
Practically no systematic work has been done to study the influence of the thyroid gland on male subfertility in the older animals. It has been observed that in the young breeding animals the thyroxin secretion rate is at its optimum, and the fertility at its peak. The male fertility declines with advancing age, and so does the thyroxin secretion rate. It was, therefore, TABLE 3.
Sexual Desire and Semen Characteristics of the Subfertile Buck Rabbits Before and During Thyroid Therapy Semen characteristics
Date of birth Rabbit
1 2 3 4 5 6 7 8 9
9.2.49 13.1.49 16.8.45 17.8.45 9.2.49 21.6.45 21.3.45 26.4.45 12.7.45
Treatment<>
0.008%TP 0.008%TP 0.008%TP 0.008% TP Controlb 0.004% TP 0.004%TP 0.008% TP Controlb
Sexual· desire
Vol. ml/ ejaculate
1.70 3.6d 0.7 0 1.3d 2.3 3.6 0.5 0.7 1.7 3.3 0.6 1.0 0.8 2.6 1.6 0.4 1.81 0.61 1.8 2.3 0.5 0.6 2.2 1.7 0.7 0.8 1.1 1.4 2.9 0.8 2.01 0.71 TP, Thyroprotein
Motility·
1.90 2.3 2.3 2.4 1.91 2.5 2.5 2.4 2.01
3.3 d 3.1 3.3 3.4
2.1 2.3 3.1
Million sperm/ml.
207" 186 210 200 1751 221 217 134 l771
394 d 380 375 351
206 218 335
Duration of treatment 8 weeks. Control throughout the lO-week experimental period. o Mean of 8 pretreatment period determinations. Ii Mean of 12 determinations after the first two weeks of thyroprotein treatment (TP). • Estimated in terms of numerical scores. 1 Mean of 20 determinations. a b
considered desirable to find out whether any relationship exists between subfertility and the decline in the thyroxin secretion rate in the older animals because it seems to have some practical value in the field of reproduction. Nine male rabbits (inbred strains), which were classed as subfertile in view of their poor breeding records, were selected (Table 3). The experimental data indicated that one of the causes of subfertility was a decrease in the thyroxin secretion rate because thyroid therapy stimulated spermatogenesis and greatly improved the libido and semen qualities of the treated animals which, before the start of the treatment, showed arrested spermato-
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THYROID AND MALE FERTILITY
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genesis, poor libido, and deterioration in semen qualities (subfertile buck rabbit-Table 3 and Figs. 17, 18, 19, 20, 21).11,16,17 It was interesting to find that thyroid therapy, by stimulating the process --. CONTROL TP. TREATE D
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Fig. 21. Graphic representation of the data on libido and semen qualities of a so-classed subfertile inbred buck rabbit in view of its poor fertility rate and another thyroprotein-treated subfertile inbred buck rabbit two weeks before and eight weeks during the treatment period. Thyroid therapy within the optimal physiologic limit considerably improved the libido and semen qualities of the treated animal. (P-T, pre-treatment period.)
of spermatogenesis in the testes of the so-classed subfertile rabbit and the young ram during the non breeding season, checked those types of sperm abnormalities which appeared to be associated with defective spermatogenesis.11, 12
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IN VITRO EFFECT OF THYROXIN ON SPERMATOZOA The addition of thyroxin in critical concentrations to bull semen samples of average density, collected by means of an artificial vagina, resulted in a significant increase in the oxygen uptake of the spermatozoa after 24-46
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TIME/M IN. Fig. 22. Effects of thyroxin on the oxygen uptake of a bull semen sample with original sperm concentration of 845 million/mI. One cc. of the semen sample, sperm suspension, or seminal plasma was diluted with 3 cc. of dialized egg yolk phosphate buffer solution, along with the specified concentration of thyroxin in a test tube, and each tube was stored for 44 hours at +5° C. The oxygen uptake was then measured manometrically by using Dixon's modification of the Barcroft manometer (I-control semen sample, 2-0.5 gamma DL-thyroxin-treated semen, 3-1.0 gamma DL-thyroxintreated semen, 4-untreated washed sperm suspension, 5-1 gamma DL-thyroxintreated washed sperm suspension, 6-control bull seminal plasma, and 7-1 gamma DL-thyroxin-treated seminal plasma).
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THYROID AND MALE FERTILITY
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hours storage at +5°C. (Fig. 22). Thyroxin treatment was only effective in the whole semen, while it had no effect on the very small oxygen uptake of seminal plasma or on the oxygen uptake of washed sperm suspensions (Fig. 22). 5 The addition of thyroxin to bull semen appears to have some practical application in the field of artificial insemination. EFFECT OF BREED AND STRAIN DIFFERENCES There are some indications that the activities of some of the endocrines may be modified favorably by selective breeding, and such modifications will result in improved reproductive ability among livestock. Mimer and Upp23 observed that "double cross" hybrid chicks produced from Rhode Island Red and White Leghorn inbred lines had a much higher thyroxin secretion rate than single cross chicks produced by crosses of two inbred lines of some breeds or than chicks resulting from aNew Hampshire and Barred Plymouth Rock mating. Moreover, cross bred offsprings were found to have a higher thyroxin secretion rate than pure-bred offsprings from Jersey Buff and Broad-Breasted Bronze turkeys.24 These studies suggest the possibility that thyroid activity may be connected with the phenomenon of hybrid vigor. DISCUSSION The present work indicates that the functions of the thyroid gland in relation to maturity and fertility in different species of animals would be better understood if they could be expressed quantitatively in terms of the amount of thyroxin that is being secreted per day by the animal at different stages of its development under specified conditions because the terms hypothyroidism and hyperthyroidism are rather broad and therefore confusing. Therefore, it is considered desirable that the estimated rate of secretion of thyroxin should be taken into account as the basis for the quantitative administration of thyroid materials to enhance those functions that appears to be associated with high thyroid activity. The mechanism whereby the thyroid gland influences various male reproductive functions in different species of animals probably involves a complex series of interactions. The mechanism of action of the thyroid hormone on the development of the male sex organs, the relation between thyrOid functions and seasonal decline in male fertility in seasonal breeders, and the relative decline in male fertility which occurs with advancing age in some species of animals have been discussed by Maqsood in the light of his own
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MAQSOOD
Fertility & Sterility
work and that of other workers.ls There are some indications that the thyroid gland may also influence the gonads through its effects on the adrenals. The adrenal cortex is linked up with that part of the complex endocrine system which influences the various reproductive processes in some species of animals. The adrenals of a hyperthyroid rat are in a state of hypersecretion. 27 The author's results indicate that an interrelationship may exist between the thyroid, adrenals, and gonads in some species of animals. s, 10 SUMMARY In general, it can be concluded that the administration of thyrOid materials within the optimal physiologic limits, keeping in view the rate of secretion of thyroxin, would be conducive to optimal sexual development and reproductive performance in the male of some species of animals. It may be of interest to mention here that there are some indications that the administration of thyroid materials within the phYSiologic limits does not seem to affect the animal adversely.2, 4, 9, 13, 20, 24, 25 Moreover, thyroid therapy suggests some interesting possibilities in the field of reproduction among man and different species of animals, in which the thyroid activity may be subnormal, due to internal or external factors. REFERENCES 1. BOGART, R, and MAYER, D. T. The relation of temperature and the thyroid to mammalian reproductive physiology. Am.]. Physiol. 147:320, 1946. 2. BORGMAN, R F., and REINEKE, E. P. The response of thyroidectomized and intact dogs to thyroidal stimulation. Am.]. Vet. Res. 11:149, 1949. 3. MAQSOOD, M. The Influence of Variations in Environmental Temperature and Thyroid Status on Growth and Sexual Development in the Male Mouse (M. S. Thesis). East Lansing, Michigan, Michigan State College, 1949. 4. MAQSOOD, M. Histological studies of the liver in hyperthyroidism. Vet. Rec. 61:305, 1949. 5. MAQSOOD, M. "In vitro effects of thyroxine on the oxygen consumption of mammalian spermatozoa." Proc. 18th Int. Physiol. Gong. Copenhagen, Denmark, 1950, p. 353. 6. MAQSOOD, M. The role of the thyroid in sexual development in the male. Nature London 166:692, 1950. 7. MAQSOOD, M. Determination of the rate of thyroxine secretion in the male rabbit. Nature London 166:735, 1950. 8. MAQSOOD, M. The effect of varying levels of thyroidal stimulation on adrenals under different environmental temperatures. ]. Endocrinol. 7:82, 1950. 9. MAQSOOD, M. Influence of thyroid status on body growth. Experientia 7: 150, 1951. 10. MAQSOOD, M. Effect of the thyroid, season and castration on adrenals. Nature London 167:323, 1951.
Vol. 5, No.4, 1954
THYROID AND MALE FERTILITY
401
11. MAQSOOD, M. Some Aspects of Thyroid Physiology in the Male (Ph.D. thesis). New York, Cambridge Univ. Press, 1951. 12. MAQSOOD, M. An abnormality of mammalian spermatozoa. Experientia 1:304, 1951. 13. MAQSOOD, M. Influence of the thyroid on body temperature of animals. J. Physiol. 115:22, 1951. 14. MAQSOOD, M. "Thyroid functions in relation to maturity and fertility in the male." Proc. Soc. Fertil. New York, Cambridge Univ. Press, 1951, p. 33. 15. MAQSOOD, M. Seasonal variations in the testis histology of the ram. Vet. Rec. 63:597, 1951. 16. MAQSOOD, M. Thyroxine therapy in male sub-fertility. Nature London 168: 466,1951. 17. MAQSOOD, M. Influence of the thyroid on spermatogenesis. Science 114:693, 1951. 18. MAQSOOD, M. Thyroid functions in relation to reproduction of mammals and birds. Bioi. Reviews 27:281, 1952. 19. MAQSOOD, M., and PARSONS, U. Influence of continuous light or darkness on sexual development in the male rabbit. Experientia (in press) . 20. MAQSOOD, M., and REINEKE, E. P. The influence of variations in environmental temperature and thyroid status on growth and feed consumption in the male mouse. Am. J. Physiol. 160:235, 1950. 21. MAQSOOD, M., and REINEKE, E. P. Influence of variations in environmental temperature and thyroid status on sexual development in the male mouse. Am.]. Physiol. 162:24, 1950. 22. McKENZIE, F. F., and BERLINER, V. The reproductive capacity of rams. Research Bull. Missouri Agric. Exper. Station No. 265, 1937. 23. MIXNER, J. P., and Upp, C. W. Increased rate of thyroxine secretion by hybrid chicks as a factor in heterosis. Poultry Science 26:389, 1947. 24. SMYTH, J. R., and Fox, T. W. The thyroxine secretion rate of turkey poults. Poultry Science 30:607, 1951. • 25. TURNER, C. W. Effect of thyroprotein feeding on the gland and organ weights of two year old White Leghorn hens. Poultry Science 27:155, 1948. 26. TURNER, C. W., and KEMPSTER, H. L. Thyroprotein-feeding to 7-year old hens. Poultry Science 28:826, 1949. 27. WALLACH, D. P., and REINEKE, E. P. The effect of varying levels of thyroidal stimulation on the ascorbic acid content of the adrenal cortex. Endocrinology 45:75, 1949.
CONSIDERABLE WORK has been done in the field of thyroid physiology, but further work is needed to elucidate the role of the thyrOid gland in the regulation of various reproductive processes in both sexes of animals. Previous workers, not realizing the importance of the thyroxin secretion rate as a basis for determining the effective dose, have administered either too little or too much thyroid material, and in consequence have reported quite contradictory results. IS In the past, factors such as breed and strain differences, sex and age of the animal, stage of sexual development, duration of the hormone administration, and seasonal variations in the environmental temperature, all of which appear to effect the thyroxin secretion rate, were not taken into consideration while studying the role of the thyroid gland in the field of reproductive physiology. Broadly speaking, the rate of secretion of thyroxin is the amount secreted into the general circulation in a given period of time under specified conditions. With the previous work in view, it was considered desirable to elucidate the role of the thyroid gland in the regulation of various male reproductive processes, and research work was carried out on the male mouse, rabbit, and ram, type species selected for the present investigation. The work reported was carried out at the Michigan State College and the University of Cambridge during the years 1948-1951.
From the Department of Physiology and Pharmacology, Michigan State College, and Animal Research Station, Cambridge University, England. The author is thankful to Dr. J. Hammond, Dr. A. Walton, and Dr. T. Mann, of the University of Cambridge, England; Professor E. P. Reineke of the Michigan State College, and Dr. S. J. Folley, of the University of Reading, England, for their help and encouragement during the course of the present work. 382
.
TABLE 1.
Effects of Continuous Thyroid Stimulation or Inhibition on Sexual Desire and Semen Qualities of Young Male Rabbit Age at Start of Experiment-4 Weeks. Treatment Period-40 Weeks
No. Group animals
Treatment
Libidoa
2.4 ± .07 2.6 ± .07 2.9 ± .OB 3.3 ± .OB
1
4
Control
2
4
0.004% TP
3
3
O.OOB%TP
3a
3
41 51
4 3
0.0080.004%TP O.l%TH Thyroidectomized
t
2.27 4.19 71 3.20U
Volume b mi·
0.59 ±.031 0.69 ±.031 0.73 ±.036 0.97 ±.036
t
2.BO
2.21' 7.56u
TP, Thyroprotein t value obtained by comparing group Nos. 2, 8, and 8a with group No. 1. a to 8 means of 15, 14, 6, 6 and 6 reading respectively. I Onset of sexual maturity was completely arrested. u Level of significance-O.l%. 71 Level of significance-l%. • Level of significance-5%.
Density" million
225 ± 13.3 252 ±13.3 331 ± 15.4 503 ± 15.4
Abnormal sperm 8 t
2.1B 3.1Bi 13.62U
Motilityd
%
2.5 ±.12 2.6 ±.12 3.0 ±.14 3.7 ±.14
27.6 ± 1.57 0.74 2.73 i
4.55 71
TH, Thiouracil
24.B
± 1.57 19.0 ± 1.B2 13.2 ± 1.B2
2.05 3.5771 5.97u
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MAQSOOD
384
THYROXIN DOSAGE AND STAGE OF SEXUAL DEVELOPMENT
Figure 1 shows that the effects of the administration of thyroprotein (iodinated casein containing 0.72 per cent L-thyroxin on bioassay) on the
2it
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Fig. 1. The influence of variations in environmental temperature and thyroid status on the weight of the testes and seminal vesicles of young male mice. Thyroprotein (TP) and thiouracil (TU) were fed on percentage basis for a period of 4 weeks under different environmental temperatures as shown in each column. In Expts. I and II the seminal vesicles were weighed after gently squeezing out the seminal fluid, while in Expts. III and IV these were weighed intact with the seminal fluid.
weights of the testes and seminal vesicles of the young male mouse, kept at environmental temperatures of 24°C. and 30°C. for a period of four weeks, varied with the dose of the hormone administered. 3 Moreover, histologic examination of the testes and seminal vesicles of the experimental mice
THYROID AND MALE FERTILITY
Vol. 5, No.4, 1954
385
. showed that the administration of moderate doses of thyroid materials stimulated spermatogenic activity and caused epithelial proliferation of the mucosa of the seminal vesicles (with numerous secretion granules) when compared with those of the control groupS.21 The administration of larger doses of thyroid materials adversely affected the development of the testes 0
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and seminal vesicles of the treated mice. Keeping in view the significance of the thyroxin secretion rate in the present investigation, it was estimated in the male rabbit at 4, 8, 16, 32, and 48 weeks of age by the thyroxin-thiouracil technic. 7 The thyroxin secretion rate increased with advancing age, but showed a decrease when calculated per 100 Gm. body weight in the growing male rabbit as shown in Fig. 2.
386
Fertility & Sterility
MAQSQOD
DURATION OF THYROXIN ADMINISTRATION
In view of these findings, it was decided to find out whether a constant dose of thyroxin should be administered throughout the growth period, or whether the dosage levels should be increased or decreased in accordance with the rate of secretion of thyroxin in order to produce precocious sexual maturity. Taking into consideration the estimated thyroxin secretion rate at
-
22 20
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Fig. 2. Histograms to show the increase in the daily rate of secretion of L-thyroxin with advancing age, and the decrease when calculated per 100 Gm. body weight in the growing inbred rabbit. (S.R.-Secretion Rate.)
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THYROID AND MALE FERTILITY
387
different age periods as the fundamental basis, the optimal doses of thyroxin which would stimulate the reproductive processes in the growing male rabbit at different ages were determined by the simultaneous administration of graded doses of thyroxin and thiouracil for short or long periods under natural environmental conditions. The effects of these treatments on the TABLE 2.
Effects of Continuous Thyroid Stimulation or Inhibition on Weights of Testes and Accessory Organs of Young Male Rabbit Age at Start of Experiment-4 Weeks. Treatment Period-40 Weeks Testes
4
2
4
3"
3
3a"
3
4
4
5
3
Weight
Weight
No.
Group animals
I
Seminal Vesicles
Treatment
(mg.)
tb
Control
5839 ± 31.4 0.004%TP 5882 ± 31.4 O.OOB%TP 5863 ± 36.2 7348 0.0080.004%TP ±36.2 O.I%TH 3024 ± 31.4 Thyroid2931 ectomized ± 36.2 TP, Thyroprotein
0.61 0.54 31.470 63.42 0 60.65 0
(mg.)
Prostate Weight
tb
(mg.)
tb
736 81B ±9.7 ±8.9 748 0.32 853 1.B2 ±B.9 ±9.7 764 1.89 859 2.10 ± 11.2 ± 10.2 898 10.960 876 4.254 ± 10.2 ± 11.2 412 22.6 0 548 21.50 tl ± 9.7 ± 8.9 442 10.B9 o 567 18.50 ± 11.2 ± 10.2 TH, Thiouracil
"Group S was fed with thyroprotein as 0.008 per cent of the ration from fourth to twentieth week and then divided into two subgroups. Subgroup 3 was continued on the same level of thyroprotein while subgroup Sa was fed with thyroprotein as 0.006 per cent of the ration till the thirty-sixth week, when the dose was further reduced to 0.004 per cent which was continued till the end of the experiment. b t value obtained by comparing groups 2 to 5 with group l. o Level of significance-O.l%. tl Level of significance-l%. 6 Level of significance-5%.
weights of the male sex organs, on the process of spermatogenesis, development of the interstitial cells, age of sexual maturity, libido, and semen qualities in the rabbit and the Suffolk sheep were determined. Continuous administration of thyroxin within the optimal phYSiologic limit resulted in precocious sexual maturity of the treated rabbits when compared with those of the control groups6, 11, 14 (Tables 1 and 2). The testes of the treated rabbits showed active spermatogenesis, and the interstitial cells appeared well developed and more numerous than those of the control or thiouracil-treated groups (Figs. 7 and 9). The epithelial cells lining the walls of the epididymal ducts appeared well developed, and
Fertility & Sterility
MAQSOOD
388
the lumina contained masses of spermatozoa (Figs. 8 and 10). The administration of thyroxin in large doses adversely affected the development and functions of the male sex organs in the young rabbits, while its administration in doses below or about equal to the estimated thyroxin secretion rate
-
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Fig. 3. Graphic representation of the data on libido and semen qualities of the control and thyroprotein-treated inbred rabbits. The administration of thyroprotein (TP) as 0.008-0.004 per cent of the ration was started at the age of 4 weeks and continued till the age of 44 weeks. Thyroid therapy resulted in precocious sexual development and improved the libido and semen qualities of the treated rabbits when compared with those of the control group. Libido and sperm motility are expressed in estimated score values.
had no effect on the various male reproductive processes. Moreover, it was observed that the continuous administration of a constant dose of thyroxin throughout the growth period was without any beneficial effect on the various male reproductive processes in the rabbit. The reason for this is that the thyroxin secretion rate increases with age,
l
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Fig. 4. Graphic representation of the data on libido and semen qualities of the control and thyroprotein-treated young Suffolk rams during the breeding and nonbreeding seasons (1949-50). Thyroprotein treatment resulted in precocious sexual maturity, considerably improved the libido and semen qualities, and prevented the seasonal decline in male fertility during the nonbreeding season when compared with those of the control group. Semen samples were collected twice a week throughout the year by means of artificial vagina. Libido and sperm motility are represented in the estimated score values and the age at the time of first ejaculate was taken as the age of onset of sexual maturity. The hours of daylight from September to August were calculated from the Nautical Almanac, 1949, for latitude 52° N (the approximate latitude of Cambridge). The mean atmospheric temperature was calculated from the daily maximum and minimum temperatures.
Fig. 5. Testis section of an 8-week-old thyroxin-treated inbred buck rabbit (experimental period 4 weeks) showing increased spermatogenic activity when compared with the controls. A number of the seminiferous tubules show cavity formation (hematoxylin and eosin stain). (X 280) Fig. 6. Testis section of an 8-week-old thiouracil-treated rabbit (experimental period 4 weeks) showing arrested spermatogenic activity when compared with the controls or thyroxin-treated ones (Fig. 7). The tubules are not yet canalized. (X 280) Fig. 7. Testis section of a 20-week-old thyroxintreated rabbit (experimental period 16 weeks), showing all stages of spermatogenesis. Note the maturing spermia attached to the Sertoli cells. (x 280)
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THYROID AND MALE FERTILITY
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and its level does not remain constant throughout the growth period in the rabbit (Fig. 2). Thyroxin, when administered within the optimal physiologic limits to 4, 12, 28, and 44-week-old rabbits for a period of 4 weeks, stimulated the various male reproductive processes when compared with those of the control or thiouracil-treated groups (Figs. 5, 6, 11 and 12).n In long term experiments, the administration of thyroxin in optimal physiologic doses, corresponding to the thyroxin secretion rate at different age periods in the rabbit, considerably improved the libido and semen quality when compared with those of the control groups (Fig. 3). The continuous administration of thyroprotein within the physiologic limits resulted in precocious sexual maturity in the Suffolk sheep, and there was considerable improvement in the libido and semen quality throughout the year when compared with those of the control group (Fig. 4). The thyroprotein-treated animals showed the onset of sexual maturity at an average age of 20.3 -f- 0.54 weeks, and the control ones at an average age of 29.0 -f- 0.67 weeks. The difference in the age of onset of sexual maturity (the age at which the first ejaculate was collected) was statistically significant (t = 10.10). EFFECTS OF THIOURACIL ADMINISTRATION The feeding of thiouracil (2-thio-6-oxypyrimidine) as 0.1 per cent of the ration to the young male mouse and rabbit at different age groups for short periods resulted in a significant decrease in the weights of the male sex organs. 1l • 21 On histologic examination, the testes showed arrested spermatogenic activity and some atrophic and degenerative changes (Fig. 9). The epididymal ducts of the thiouracil-treated rabbits were poorly developed and contained some degenerated spermatogenic cells (Fig. 10). Some degree of desquamation and inactivity of the epithelial cells lining the Fig. 8. Epididymis section of a 20-week-old thyroxin-treated rabbit (same as in Fig. 9), showing a mass of sperm in the cavity. The epithelial cells lining the ducts Fig. 9. Testis show an increase in cell height (compare with Fig. 10). (X 280) section of a 20-week-old thiouracil-treated rabbit (experimental period 16 weeks) showing arrested process of spermatogenesis. The spermatogenic cells show atrophic and degenerative changes. Some of the sloughed off cells are seen free in the lumina of tubules. (X 280) Fig. 10. Epididymis section of a 20-week-old thiouraciltreated male rabbit (same as in Fig. 9), showing the presence of degenerated spermatogenic cells in the ducts. The epithelial cells lining the ducts show a decrease in cell height. (X 280)
Fig. 11. Testis section of a 32-week-old thiouracil-treated rabbit (experimental period 4 weeks) showing some degree of arrested spermatogenic activity in the seminiferous tubules. The cavities of the tubules contain protoplasmic debris. (X 280) Fig. 12. Testis section of a 32-week-old thyroxin-treated rabbit (experimental period 4 weeks) showing increased spermatogenic activity when compared with the control ones. The maturing spermia appear to be better developed (compare with Fig. 11). (X 280) Fig. 13. Testis section of a young SuHolk ram during the breeding season showing the degree of spermatogenic activity (compare with Fig. 16).
,
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THYROID AND MALE FERTILITY
393
mucosa of the seminal vesicles of the mouse was also observed. Accumulation of these desquamated cells in the seminal fluid was seen in the lumina of the seminal vesicles. 21 Prolonged thiouracil treatment or thyroidectomy in the young male rabbit and sheep arrested the onset of sexual maturity, and the treated animals neither showed any libido nor produced any ejaculateY Lack of sexual desire and arrested growth of the accessory male sex organs of the treated animals also indicated interference with the production of the male sex hormone by the interstitial cells, which showed a considerable decrease in number. The degree of impairment of the various male reproductive processes varied with the age of the animal, and with dose and duration of the treatment period. Figure 16 shows the effects of the administration of thiouracil on the histology of the testis of the ram for a period of about 12 monthsY Histologic studies of the testes of the thiouracil-treated rams indicate that the degree of impairment of the normal process of spermatogenesis becomes more and more pronounced with the prolongation of the treatment period. The adverse effects of thiouracil treatment or thyrOidectomy were more marked in the younger animals than the older ones because the demand for thyroxin for the development of the various physiologic processes is. comparatively higher in the younger animals. It was interesting to find that the administration of thyroxin, in amounts about equal to the estimated thyroxin secretion rate in the growing male rabbit simultaneously fed with 0.1 per cent thiouracil as part of the ration, maintained the male reproductive processes up to those of the control groups. The results obtained demonstrated rather clearly that the level of thyroxin (x 280) Fig. 14. Testis section of a 16-month-old control ram (during the nonbreeding season) showing arrested spermatogenesis, with some maturing spermia attached to the Sertoli cells, in some of the seminiferous tubules. The interstitial cells show a comparative decrease in number. (x 280) Fig. 15. Testis section of a 16-month-old thyroxin-treated ram (during nonbreeding season) showing active spermatogenesis in majority of the tubules. Note a large mass of maturing spermia in the tubules. The interstitial cells appear well developed (compare with Figs. 13 and 14). (X 280) Fig. 16. Testis section of a 16-month-old thiouracil-treated Suffolk ram (after 12 months of thiouracil treatment). Note the spermatogenic cells are sloughed off in practically all of the seminiferous tubules and the tubules contain a syncytium of Sertoli cells. The tubules have greatly decreased in diameter. Some remains of the degenerated spermatogenic cells are still seen in some of the tubules. (x 280)
394
MAQSOOD
Fertility & Sterility
in the blood has a pronounced influence on the development and functions of the male sex organs in the growing animals. This is because the administration of thyroxin in amounts below or about equal to the estimated thyroxin secretion rate in the growing animals was ineffective, since such amounts of exogenous thyroxin simply depressed the production of the thyrotrophic hormone, with the result that the endogenous thyroxin level was reduced by an amount equivalent to the exogenous thyroxin administered. In such cases, the final level of thyroxin in the blood remained the same. Moreover, any intederence with the normal production of the thyroid hormone by the thyroid gland, such as administration of thiouracil or thyroidectomy, adversely affected the various male reproductive processes in young animals.
EFFECT OF SEASONAL VARIATIONS The experimental data indicated that during the period of seasonal decline in male fertility, the so-called "summer sterility" in the ram, there occurs a decrease in the thyroxin secretion rate since the continuous administration of thyroxin in optimal physiologic doses throughout the year practically maintained the male reproductive processes during the nonbreeding season to those levels observed during the breeding season (Fig. 4),11 This evidence was obtained by evaluating the libido and semen qualities, and by histologic examination of the testes of the treated and control rams during the breeding and nonbreeding seasons. During the non breeding season, the testes of the Suffolk ram in Cambridge, England, showed limited spermatogenesis and a decrease in the number of the interstitial cells, while the testes of the thyroxin-treated rams showed active spermatogenesis, and the interstitial cells were numerous and well developed (Figs. 14 and 15) Y The so-called "summer sterility" in the ram which occurs during the summer months in the United States is due to high environmental temperature. 1 , 22 An increase of only 6°C. from 24°C. to SO°C. in the environmental temperature resulted in atrophic and degenerated changes in the testes and seminal vesicles of the young male mouse. 21 Moreover, the length of daylight does not appear to affect the weight, histology, and functions of the male sex organs in the rabbit (inbred strains) at different age periods. 19 During the summer months, the rate of secretion of thyroxin declines Significantly below the winter value in the young male rabbit, and it was interesting to find that during this period there occurred a decline in male fertility,11 It was observed that the administration of thyroxin within the optimal physio-
Vol. 5, No.4, 1954
THYROID AND MALE FERTILITY
395
logic limits considerably improved the various male reproductive processes in the young male rabbit during the summer months. Thyroxin therapy also improved the libido and fertility rate in a young Essex boar (inbred) which
Fig. 17. Stained semen smear from a so-classed subfertile buck rabbit, showing tailless sperm. (x 1300) Fig. 18. Stained semen smear from a previously subfertile buck rabbit after thyroid therapy. Note a marked decrease in the number of abnormal sperm (compare with Fig. 17). (X 1100) Fig. 19. Testis section of a subfertile buck rabbit, showing arrested spermatogenesis and the presence of a few giant cells. Note a marked decrease in the number of interstitial cells. (X 280) Fig. 20. Testis section of a subfertile buck rabbit after thyroid therapy showing a marked improvement in the process of spermatogenesis. The tubules contain numerous maturing spermia (compare with Fig. 19). (X 280)
before the start of the treatment showed very poor libido and a decline in fertility during the summer.1S These studies indicate that high environmental temperature adversely affects the male reproductive processes in some species of animals, and that
396
fertility & Sterility
MAQSOOD
the thyroid gland may be the physiologic medium through which seasona] variations affect the male reproductive processes. EFFECT OF AGE VARIATIONS
Practically no systematic work has been done to study the influence of the thyroid gland on male subfertility in the older animals. It has been observed that in the young breeding animals the thyroxin secretion rate is at its optimum, and the fertility at its peak. The male fertility declines with advancing age, and so does the thyroxin secretion rate. It was, therefore, TABLE 3.
Sexual Desire and Semen Characteristics of the Subfertile Buck Rabbits Before and During Thyroid Therapy Semen characteristics
Date of birth Rabbit
1 2 3 4 5 6 7 8 9
9.2.49 13.1.49 16.8.45 17.8.45 9.2.49 21.6.45 21.3.45 26.4.45 12.7.45
Treatment<>
0.008%TP 0.008%TP 0.008%TP 0.008% TP Controlb 0.004% TP 0.004%TP 0.008% TP Controlb
Sexual· desire
Vol. ml/ ejaculate
1.70 3.6d 0.7 0 1.3d 2.3 3.6 0.5 0.7 1.7 3.3 0.6 1.0 0.8 2.6 1.6 0.4 1.81 0.61 1.8 2.3 0.5 0.6 2.2 1.7 0.7 0.8 1.1 1.4 2.9 0.8 2.01 0.71 TP, Thyroprotein
Motility·
1.90 2.3 2.3 2.4 1.91 2.5 2.5 2.4 2.01
3.3 d 3.1 3.3 3.4
2.1 2.3 3.1
Million sperm/ml.
207" 186 210 200 1751 221 217 134 l771
394 d 380 375 351
206 218 335
Duration of treatment 8 weeks. Control throughout the lO-week experimental period. o Mean of 8 pretreatment period determinations. Ii Mean of 12 determinations after the first two weeks of thyroprotein treatment (TP). • Estimated in terms of numerical scores. 1 Mean of 20 determinations. a b
considered desirable to find out whether any relationship exists between subfertility and the decline in the thyroxin secretion rate in the older animals because it seems to have some practical value in the field of reproduction. Nine male rabbits (inbred strains), which were classed as subfertile in view of their poor breeding records, were selected (Table 3). The experimental data indicated that one of the causes of subfertility was a decrease in the thyroxin secretion rate because thyroid therapy stimulated spermatogenesis and greatly improved the libido and semen qualities of the treated animals which, before the start of the treatment, showed arrested spermato-
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genesis, poor libido, and deterioration in semen qualities (subfertile buck rabbit-Table 3 and Figs. 17, 18, 19, 20, 21).11,16,17 It was interesting to find that thyroid therapy, by stimulating the process --. CONTROL TP. TREATE D
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of spermatogenesis in the testes of the so-classed subfertile rabbit and the young ram during the non breeding season, checked those types of sperm abnormalities which appeared to be associated with defective spermatogenesis.11, 12
Fertility & Srerility
MAQSOOD
398
IN VITRO EFFECT OF THYROXIN ON SPERMATOZOA The addition of thyroxin in critical concentrations to bull semen samples of average density, collected by means of an artificial vagina, resulted in a significant increase in the oxygen uptake of the spermatozoa after 24-46
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TIME/M IN. Fig. 22. Effects of thyroxin on the oxygen uptake of a bull semen sample with original sperm concentration of 845 million/mI. One cc. of the semen sample, sperm suspension, or seminal plasma was diluted with 3 cc. of dialized egg yolk phosphate buffer solution, along with the specified concentration of thyroxin in a test tube, and each tube was stored for 44 hours at +5° C. The oxygen uptake was then measured manometrically by using Dixon's modification of the Barcroft manometer (I-control semen sample, 2-0.5 gamma DL-thyroxin-treated semen, 3-1.0 gamma DL-thyroxintreated semen, 4-untreated washed sperm suspension, 5-1 gamma DL-thyroxintreated washed sperm suspension, 6-control bull seminal plasma, and 7-1 gamma DL-thyroxin-treated seminal plasma).
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THYROID AND MALE FERTILITY
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hours storage at +5°C. (Fig. 22). Thyroxin treatment was only effective in the whole semen, while it had no effect on the very small oxygen uptake of seminal plasma or on the oxygen uptake of washed sperm suspensions (Fig. 22). 5 The addition of thyroxin to bull semen appears to have some practical application in the field of artificial insemination. EFFECT OF BREED AND STRAIN DIFFERENCES There are some indications that the activities of some of the endocrines may be modified favorably by selective breeding, and such modifications will result in improved reproductive ability among livestock. Mimer and Upp23 observed that "double cross" hybrid chicks produced from Rhode Island Red and White Leghorn inbred lines had a much higher thyroxin secretion rate than single cross chicks produced by crosses of two inbred lines of some breeds or than chicks resulting from aNew Hampshire and Barred Plymouth Rock mating. Moreover, cross bred offsprings were found to have a higher thyroxin secretion rate than pure-bred offsprings from Jersey Buff and Broad-Breasted Bronze turkeys.24 These studies suggest the possibility that thyroid activity may be connected with the phenomenon of hybrid vigor. DISCUSSION The present work indicates that the functions of the thyroid gland in relation to maturity and fertility in different species of animals would be better understood if they could be expressed quantitatively in terms of the amount of thyroxin that is being secreted per day by the animal at different stages of its development under specified conditions because the terms hypothyroidism and hyperthyroidism are rather broad and therefore confusing. Therefore, it is considered desirable that the estimated rate of secretion of thyroxin should be taken into account as the basis for the quantitative administration of thyroid materials to enhance those functions that appears to be associated with high thyroid activity. The mechanism whereby the thyroid gland influences various male reproductive functions in different species of animals probably involves a complex series of interactions. The mechanism of action of the thyroid hormone on the development of the male sex organs, the relation between thyrOid functions and seasonal decline in male fertility in seasonal breeders, and the relative decline in male fertility which occurs with advancing age in some species of animals have been discussed by Maqsood in the light of his own
400
MAQSOOD
Fertility & Sterility
work and that of other workers.ls There are some indications that the thyroid gland may also influence the gonads through its effects on the adrenals. The adrenal cortex is linked up with that part of the complex endocrine system which influences the various reproductive processes in some species of animals. The adrenals of a hyperthyroid rat are in a state of hypersecretion. 27 The author's results indicate that an interrelationship may exist between the thyroid, adrenals, and gonads in some species of animals. s, 10 SUMMARY In general, it can be concluded that the administration of thyrOid materials within the optimal physiologic limits, keeping in view the rate of secretion of thyroxin, would be conducive to optimal sexual development and reproductive performance in the male of some species of animals. It may be of interest to mention here that there are some indications that the administration of thyroid materials within the phYSiologic limits does not seem to affect the animal adversely.2, 4, 9, 13, 20, 24, 25 Moreover, thyroid therapy suggests some interesting possibilities in the field of reproduction among man and different species of animals, in which the thyroid activity may be subnormal, due to internal or external factors. REFERENCES 1. BOGART, R, and MAYER, D. T. The relation of temperature and the thyroid to mammalian reproductive physiology. Am.]. Physiol. 147:320, 1946. 2. BORGMAN, R F., and REINEKE, E. P. The response of thyroidectomized and intact dogs to thyroidal stimulation. Am.]. Vet. Res. 11:149, 1949. 3. MAQSOOD, M. The Influence of Variations in Environmental Temperature and Thyroid Status on Growth and Sexual Development in the Male Mouse (M. S. Thesis). East Lansing, Michigan, Michigan State College, 1949. 4. MAQSOOD, M. Histological studies of the liver in hyperthyroidism. Vet. Rec. 61:305, 1949. 5. MAQSOOD, M. "In vitro effects of thyroxine on the oxygen consumption of mammalian spermatozoa." Proc. 18th Int. Physiol. Gong. Copenhagen, Denmark, 1950, p. 353. 6. MAQSOOD, M. The role of the thyroid in sexual development in the male. Nature London 166:692, 1950. 7. MAQSOOD, M. Determination of the rate of thyroxine secretion in the male rabbit. Nature London 166:735, 1950. 8. MAQSOOD, M. The effect of varying levels of thyroidal stimulation on adrenals under different environmental temperatures. ]. Endocrinol. 7:82, 1950. 9. MAQSOOD, M. Influence of thyroid status on body growth. Experientia 7: 150, 1951. 10. MAQSOOD, M. Effect of the thyroid, season and castration on adrenals. Nature London 167:323, 1951.
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11. MAQSOOD, M. Some Aspects of Thyroid Physiology in the Male (Ph.D. thesis). New York, Cambridge Univ. Press, 1951. 12. MAQSOOD, M. An abnormality of mammalian spermatozoa. Experientia 1:304, 1951. 13. MAQSOOD, M. Influence of the thyroid on body temperature of animals. J. Physiol. 115:22, 1951. 14. MAQSOOD, M. "Thyroid functions in relation to maturity and fertility in the male." Proc. Soc. Fertil. New York, Cambridge Univ. Press, 1951, p. 33. 15. MAQSOOD, M. Seasonal variations in the testis histology of the ram. Vet. Rec. 63:597, 1951. 16. MAQSOOD, M. Thyroxine therapy in male sub-fertility. Nature London 168: 466,1951. 17. MAQSOOD, M. Influence of the thyroid on spermatogenesis. Science 114:693, 1951. 18. MAQSOOD, M. Thyroid functions in relation to reproduction of mammals and birds. Bioi. Reviews 27:281, 1952. 19. MAQSOOD, M., and PARSONS, U. Influence of continuous light or darkness on sexual development in the male rabbit. Experientia (in press) . 20. MAQSOOD, M., and REINEKE, E. P. The influence of variations in environmental temperature and thyroid status on growth and feed consumption in the male mouse. Am. J. Physiol. 160:235, 1950. 21. MAQSOOD, M., and REINEKE, E. P. Influence of variations in environmental temperature and thyroid status on sexual development in the male mouse. Am.]. Physiol. 162:24, 1950. 22. McKENZIE, F. F., and BERLINER, V. The reproductive capacity of rams. Research Bull. Missouri Agric. Exper. Station No. 265, 1937. 23. MIXNER, J. P., and Upp, C. W. Increased rate of thyroxine secretion by hybrid chicks as a factor in heterosis. Poultry Science 26:389, 1947. 24. SMYTH, J. R., and Fox, T. W. The thyroxine secretion rate of turkey poults. Poultry Science 30:607, 1951. • 25. TURNER, C. W. Effect of thyroprotein feeding on the gland and organ weights of two year old White Leghorn hens. Poultry Science 27:155, 1948. 26. TURNER, C. W., and KEMPSTER, H. L. Thyroprotein-feeding to 7-year old hens. Poultry Science 28:826, 1949. 27. WALLACH, D. P., and REINEKE, E. P. The effect of varying levels of thyroidal stimulation on the ascorbic acid content of the adrenal cortex. Endocrinology 45:75, 1949.