CORRELATED RESPONSES IN MALE REPRODUCTIVE TRAITS IN MICE SELECTED FOR LITTER SIZE

AND BODY WEIGHT1

E. J. EISEN AND B. H. JOHNSON

Department of Animal Science, North Carolina State University, Raleigh, North Carolina 27650

Manuscript received May 22, 1981 Revised copy received September 8, 1981

ABSTRACT

Correlated responses in male reproductive traits were determined at 4, 6 and 8 weeks of age in lines of mice selected for large litter size (L+), large 6-week body weight (W+) , large litter size and small body weight (L+W-) and small litter size and large body weight (L-W+), and in an unselected control (K). Concentration of serum testosterone and weights of testes, seminal vesicles, epididymides and adrenal glands increased with age. Line differences in testosterone concentration were not detected. L+ and W+ males exhibited positive correlated responses in testes, epididymides and seminal vesicle weights. Testis weight adjusted for body weight was significantly larger for L + than controls and approached significance for Wf . Realized genetic correlation be- testis weight and litter size was 0.60 rt 0.04, and the realized partial genetic correlation holding body weight constant was 0.42. Therefore, pleiotropic loci, acting via the hypothalamic-pituitary axis, affect testis weight and litter size independently of body weight. Additionally, genes influencing overall growth have a pleiotropic effect on testis weight and litter size in mice; the realized genetic correlations of body weight with testis weight and with litter size were 0.60 0.03 and 0.52 +- 0.10. Testis weight increased in both L+W- and L-W+ males. The positive correlated response in L+W- may have resulted from changes in frequency of genes controlling reproductive processes; whereas, in L-W+ it could have been the result of changes in the frequency of genes associated with body weight.

HE gonadotrophic and gonadotrophic-releasing hormones play a major role in controlling gonadal function in male and female mammals. Genetic differ-

ences among four inbred strains of mice have been shown for pituitary luteinizing hormone (LH) level, serum LH level and induced LH release (SUSTARIC and WOLFE 1979). Based on the premise that genes that control synthesis of gonado- trophic hormones are expressed in both sexes, LAND (1973) postulated that re- productive characters in males and females may be genetically correlated. He presented two sources of evidence to support this argument. Testis weight in mice selected for increased or decreased ovulation rate diverged in the same direction as ovulation rate, and testis diameter in sheep was greater in the breed with the

1 Paper No. 6929 of the Journal Series of the North Carolina Agricultural Research Service Raleigh. The use of trade names in this publication does not imply endorsement by the North Carolina Agriculturh Research Service of the products named, nor criticism of similar ones not mentloned.

Genetics 99: 513-524 NovemberiDecember, 1981.

514 E. J. E I S E N A N D B. H. J O H N S O N

higher ovulation rate. Selection for testis weight in mice resulted in a positive correlated response in ovulation rate (ISLAM, HILL and LAND 1976). The practical significance of these findings is that it may be possible to increase reproductive performance in livestock by selecting for some measure of reproduction in the male. Since fewer males than females are required as replacement animals, the selection intemity is greater; hence, the rate of genetic improvement can be in- creased. Also, the low heritability of reproductive characters usually encountered in females may be circumvented by selecting in the male. However, the magni- tude of the genetic correlation between male and female reproductive characters must be established before this approach can be applied satisfactorily. LAND, CARR and LEE (1980) have reviewed the status of research in this field.

The present paper describes correlated responses in male reproductive traits in lines of mice selected for litter size and/or body weight using single-trait or index selection. Because both litter size and testis weight are phenotypically and genetically positively correlated with body weight, inclusion of the index lines provides additional information about the interrelationship among these traits.

MATERIALS A N D METHODS

The five lines used in this study were developed by individual selection based on measure- ments in females only (EISEN 1978). The selection criteria in the four selected lines were: L+, large litter size at birth; W+, large 6-week body weight; L-W+, small litter size and large body weight; L+W-, large litter size and small body weight. A randomly selected control line (K) was maintained contemporaneously.

Male and female mice were randomly selected from the 22nd generation of selection and randomly pair-mated within each line. All of these mice had already produced a litter. Females were caged singly after 16 days of cohabitation and checked daily for evidence of parturition. Litters were standardized to eight mice on the day of birth, attempting to maximize the number of male pups. Progeny were weaned at 3 weeks of age and reared in groups of four mice per cage.

Male progeny from each litter were randomly assigned to be killed at 4, 6 or 8 weeks of age. Body weights were recorded at each age. Peripheral blood samples were collected by heart puncture and serum concentrations of testosterone determined by radioimmunoassay (WELSH, MCCRAW and JOHNSON 1979). Mice were then killed with ether, and testes, epididymides, seminal vesicles and adrenal glands were excised, trimmed of adhering tissue and placed in a petri dish on filter paper moistened with saline. The tissues were weighed after all animals had been necropsied on a particular day.

Purina Mouse Chow was fed ad libitum from mating through lactation and Purina Laboratory Chow was fed ad Zibiium after weaning. The laboratory was maintained at 21" i I", 50-60% relative humidity and a 12 hr light: 12 hr dark cycle.

The data were analyzed using least-squares analysis of variance for unequal subclasses (HARVEY 1975). Organ weights were adjusted for body weights by analysis of covariance. Sig- nificance of differences between line means was determined by single degree-of-freedom t-tests.

TO determine i f the growth of each organ relative to body weight differed among lines, the natural logarithms (In) of testis, epididymis, seminal vesicle and adrenal gland weights were regressed on In body weight fo r each line. Differences among regression coefficients were determined in the same way as differences among means.

RESULTS

Litter size: The mean litter size of each line in generation 22 represents the cumulative effects of selection (Table 1 ) . Single-trait selection for increased litter

CORRELATED RESPONSES IN MICE 515

TABLE 1

First parity litter size in generation 22 of selection

Line No. of mice Mean f S.E.t

L+ 100 16.4 t- 0.358 W + 87 13.8 t- 0.38b L+W- 75 14.1 -Ir 0.41b K 101 12.6 t- 0.35c L-w + 69 10.5 t- 0.42d

a$b!c.dMeans not sharing a common superscript are significantly different at P < 0.05. + Standard error of the mean.

size in the L+ line yielded a direct response of 30% above the K control line ( P < 0.05). The correlated response in litter size due to selection for 6-week body weight was 10% in the Wf line ( P < 0.05). Litter size diverged ( P < 0.05) in the expected direction in the LfW- and L-W+ lines. These data agree with re- sults reported in earlier generations of selection (EISEN 1978; DURRANT, EISEN and ULBERG 1980).

Body weight: Differences among lines in male body weight at generation 22 of selection were apparent at 4 weeks of age (Table 2) ; W+ mice were larger (P < 0.05) than all other lines, LfW- mice were smaller ( P < 0.05) than mice from other lines, and L+ and L-W+ mice did not differ significantly from the control line. Body weight differences associated with selection were well estab- lished at 6 weeks of age and were maintained through 8 weeks. The direct re- sponse in 6-week body weight was 35% in the Wf line ( P < 0.05) ; whereas, the L+ line had a correlated response of 9% ( P < 0.05). The index lines diverged ( P < 0.05) in the intended direction. The line differences in male body weight are similar to differences reported for females in earlier generations of selection (DURRANT, EISEN and ULBERG 1980).

Organ weights: Mean organ weights by line and age are given in Table 3.

TABLE 2

Mean body weights ( g ) of males in each line at 4 , 6 and 8 weeks of age

Line

L+ W+ L-w + K L + W - S.E.$ C.V.S

Age 4 weeks 6 weeks 8 weeks

23.4% (SO)+ 35.4" (53)+ 40.q (26)+ 28.4b (74) 43.7b (4Q) 48.8b (24) 23.2" (66) 37.OC (43) 42.5c (23) 22.3" (80) 32.4 (53) 36.0d (26) 20.4.c (81) 28.9e (54) 31.7e (27)

0.4 0.4 0.6 14.8 7.6 8.0

a , b , e , d , e Column means with no superscripts in common are significantly different at P < 0.05. t Sample size in parentheses. $ Approximate standard error of the mean. $ Coefficient of variation.

516 E. J. EISEN AND B. H. JOHNSON

TABLE 3

Mean organ weights (mg) of males in each line at 4 , 6 and 8 weeks ~ ~ ~~

4 weeks 6 weeks 8 weeks I _ _ - ~ 4 weeks G weeks 8 weeks

Line Testes Epididymides

L+ W+ L-w + K L+W- S.E.$ c .v .g

L+ W+ L-W + K L+W- S.E.2 c.v.g

110.5" (27)f 185.za (27)f 129.0b (26) 201.6b (25) 121.5b ( 2 3 ) 188.4" (20) 98.OC (27) 157.2c (27)

101.3c (27) 190.7ab (27) 3.6 4.5

16.2 12.2

Seminal uesicles 35.0a 137.5" 46.7b 185.6b 29.6aC 120.4aC 26.6c 105.8c 27.6c 124.cmac

2.6 7.2 32.2 26.9

193.7" (26)f 212.2b (24) 202.7ab (23) 170.5c : (2.6) 211.8b : (27)

5.2 13.2

190.58 245.4b 177.1BC 152.7C 165.W

9.7 26.3

244.5ac 54.6" 65.9ab 28.3b 65.9b 80.4c 26.6ab 52.18 68.8b 23.7c 46.7c 59.7" 25.1aC 52.0" 66.8b

0.94 1.33 2.44 18.6 12.2 17.9

Adrenal glands 5.48" 8.76a 7.3816 6.31b 9.328 7.77" 5.93ab 9.078 8.24 5.36c 8.27a 7.14s 5.97ab 9.09a 7.62" 0.25 0.32 0.34

21.6 17.7 22.5

a p b ~ c Column means with no superscripts in common are significantly different at P < 0.05. f Sample size in parentheses. $Approximate standard error of the mean. $ Coefficient of variation.

Organ weights within each age group also were compared after adjustment to a constant body weight by covariance analysis (Table 4). Preliminary analyses in- dicated that regression coefficients of the weight of each organ on body weight were homogeneous across lines within ages, and the pooled regressions did not deviate significantly from linearity.

Testis, epididymis, seminal vesicle and adrenal gland weights increased ( P < 0.01) with age, except for a decrease in adrenal weights from 6 to 8 weeks. The L+ line exhibited positive correlated responses ( P < 0.05) in testis weight at 4, 6 and 8 weeks of age. Adjusting testis weight to a constant body weight reduced the magnitude of the correlated responses, but they were still significant ( P < 0.05) at 4 and 6 weeks and approached significance at 8 weeks. Positive corre- lated responses ( P < 0.05) in testis weight were apparent in W+ males. Follow- ing adjustment for body weight, W+ exceeded K males in testis weight at 4, 6 and 8 weeks, but the differences were not significant at 6 and 8 weeks. L+ W- and L-W+ mice had positive correlated responses (P < 0.05) in unadjusted testis weights at all ages, except for unadjusted testis weight at 4 weeks in L+W-. The L+W- and L-W+ lines have positive correlated responses in corrected testis weight as well.

The L+ and W+ lines were observed to have positive correlated responses in epididymis and seminal vesicle weights at each age. When compared at a con- stant body weight, however, the differences were not significant. At 4 weeks of age, L+W- and K males had similar epididymis and seminal vesicle weights, but L+W- males had larger organ weights at 6 and 8 weeks, the difference being

CORRELATED RESPONSES IN MICE

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518 E. 3. EISEN AND B. H. J O H N S O N

significant ( P < 0.05) for epididymis weight only. When adjusted for body weight, L+W- mice had significantly (P < 0.05) larger epididymides and seminal vesicles as compared with those of K mice. The epididymis and seminal vesicle weights of L-W+ lines exhibited positive correlated responses at all ages, but only epididymis weights were significant. Epididymis and seminal vesicle weights of L-W+ and K mice did not differ significantly after adjustment for body weight.

Adrenal gland weights did not show any consistent line differences. Growth rate of organs reltrtiue to overall growth rate: Growth rate of a specific

body tissue relative to growth rate of the total body provides an indicaion of rela- tive rate of tissue development. This was estimated by the regression of In organ weight on In body weight from 4 to 8 weeks of age (Table 5 ) . Relative rate of testis development did not change in the L+ line, when compared with the K line, but rate of testis development relative to overall growth was reduced ( P < 0.05) in the W+ line. The regression coefficient of In testis weight on In body weight was higher ( P < 0.05) in L+W- and lower ( P < 0.05) in L-W+ when compared with the control line. The regressions of epididymis weight and seminal vesicle weight on body weight were smaller (P < 0.05) in the L-Wf line than in the control line. Rate of development of the seminal vesicle was slower in the L+ and W+ lines than in the control line. No significant line differences were observed among the regression coefficients of In adrenal weight on In body weight.

Testosterane concvmtration: Line differences in the percent of males that had a detectable concentration (2 0.25 ng/ml) of serum testosterone at 4 and 6 weeks of age were not significant (Table 6). At 8 weeks of age, all males scored had a measurable concentration of testosterone, except for five (18%) L+W- mice. This result was probably a chance event since only 7% of L+ W- males had non- detectable concentrations of testosterone at 6 weeks.

Mean serum concentrations of testosterone levels are presented in Table 7. The means and variances of testosterone concentration were positively correlated. Individual variation was extremely high; coefficients of variation ranged from 70.1 to 97.1 %. The data were transformed to natural logarithms to stabilize the variances. Analysis of variance indicated that In concentrations of testosterone

TABLE 5

Linear regression coeflcients (b t S.E.) (ln mg/ln g ) of In organ weight on In body weight from 4 to 8 weeks of age for each line

~ ~~~

Epididymdes Seminal vesicles Adrenal glands Line Testes

L+ 1.01 2 0.06ab 1.69 t 0.068 3.16 t 0.12ab 0.67 t 0.W W+ 0.84 t 0.078 1.76 I 0.07a 3.16 k 0.13ab 0.60 +- 0.1oa L-w + 0.84 t 0.07a 1.49 t 0.07b 2.94 F 0.13a 0.65 i. 0.10”

1.06 t- 0.07b 1.69 t 0.07a 3.30 t 0.13b 0.78 2 O.l@ K L+W- 1.37 F 0.07C 1.70 2 0.07a 3.32 +- 0.13b 0.58 t 0.1Oa

b, c Column regressions with no superscripts in common are significantly different a t P < 0.05.

CORRELATED RESPONSES IN M I C E 519

TABLE 6

Percent of males with detectable concentrations of serum testosterone at 4 , 6 and 8 weeks of age+

4 weeks 6 weeks 8 weeks Line N % N % N .. %

L+ 27 51.8 27 81.5 26 100.0 W+ 25 32.0 25 84.0 24 100.0 L-W+ 23 47.8 21 100.0 23 100.0 K 27 55.6 27 85.2 26 100.0 L+W- 27 70.4 27 92.6 22 81.5 Chi-square$ 7.95"s 4.73"s NA (d.f. = 4)

t 2 n d m l . $ NS = not significant ( P > 0.05).

NA = not applicable.

TABLE 7

Mean serum testosterone concentrations + S.E. (ng/ml)+

Age Line 4 weeks 6 weeks 8 weeks

L+ 2.51 i 0.65 (14)$ 3.68 3z 0.75 (22)$ 4.92 ?z 0.87 (26)$ W+ 2.57 t 0.85 (8) 5.20 * 1.09 (20) 5.99 f 0.96 (24) L-W + 4.08 f 0.95 (11) 4.93 f 1.05 (20) 7.31 t 1.09 (22) K 3.31 + 0.64 (15) 4.31 f 1.09 (23) 5.19 t 0.94 (26) LkW- 3.27 t 0.63 (18) 6.17 f 0.91 (25) 4.50 k 0.89 (22)

+ Data were transformed to natural logarithms to eliminate the positive correlation between

2 Simple size in parentheses. mean and variance. No significant line differences were obtained within each age period.

increased linearly from 4 to 8 weeks of age, and there were no significant line or line-by-age interactions.

DISCUSSION

The observed positive change in testis weight following selection for large litter size agrees with the bi-directional selection experiment for litter size in mice re- ported by JOAKIMSEN and BAKER (1977). The high litter-size line in both studies showed an increase in testis weight of approximately 14 to 18% above that of the control line. Selection for high and low natural and high and low induced ovulation rate in mice caused testis weight to change in the same direction as ovulation rate (LAND 1973). Conversely, selection for high and low testis weight led to a change in ovulation rate in the same direction as testis weight (ISLAM, HILL and LAND 1976). Selection in mice for either natural ovulation rate or testis weight, however, did not change litter size because of compensatory changes in embryo mortality (LAND and FALCONER 1969; ISLAM, HILL and LAND 1976). Selection for high ovulation rate in pigs follows the same pattern of positive cor-

520 E. J. EISEN AND B. H. J O H N S O N

related response in testis size (PROUD et al. 1976) and no change in litter size (CUNNINGHAM et al. 1979). LAND, CARR and LEE (1980) found that selection for high and low testis diameter in sheep caused ovulation rate and litter size per ewe to diverge in the same direction as testis weight. I t is feasible, therefore, to change reproduction characters in the male by selecting for reproductive traits in the female, and vicg versa. These observations support LAND'S (1973) hypothesis that reproductive traits in male and female mammals have a common genetic basis.

The next step is to measure quantitatively the degree of pleiotropy between male and female characteristics. Testis weight in the male and litter size in the female were the representative traits chosen. The realized genetic correlation measures the linear rela tionship between the additive genetic effects of genes influencing two traits. The realized genetic correlation between 6-week testis weight in the male (7') and litter size in the female ( L ) was calculated from the formula (DICKERSON 1969)

(AGT.L) hL UPL

where AGT.L = correlated response in 6-week testis weight in the L+ line = 185.2 - 157.2 = 28 mg (Table 3) , A G ~ . ~ = direct response in litter size in the L+ line = 16.4 - 12.6 = 3.8 mice (Table l ) , hi = realized heritability for litter size = 0.16 +- 0.03 (EISEN 1978), h2,= realized heritability for testis weight = 0.52 0.07 (ISLAM, HILL and LAND 1976), and U: = 12.25 U: = 577 are the

phenotypic variances for litter size and testis weight in the L+ line. Substituting these values into the equation for rG T L = 0.60 2 0.04. The approximate standard error of the realized genetic correlation is based on the formula derived by HILL (1971). Thus, approximately 36% of the additive genetic variation in litter size can be explained by additive genetic variation in testis weight.

Since both litter size and testis weight are positively correlated with body weight, it is important to determine the realized partial genetic correlation be- tween testis weight and litter size, holding body weight constant. To calculate the partial correlation, it is first necessary to estimate the realized genetic corre- lation between 6-week body weight ( W ) and testis weight from the direct and correlated responses in the W+ line,

L T

(AGT W ) h v UP,

where the responses and phenotypic variances refer to the W+ line; AGT.rv = 201.6 - 157.2 = 44.4 mg (Table 3), A G ~ . ~ ~ = 43.7 - 32.4 = 11.3 g (Table 2), h", = 0.44 = 0.52 -t 0.07 (ISLAM, HILL and LAND 1976), = 7.94 and u2 = 288. Substituting these values into the above for-

mula, raTw = O.6Ow -+ 0.03. The realized genetic correlation between testis weight

0.07 (EISEN 1978),

uJk pT

CORRELATED RESPONSES IN M I C E 521

and 6-week body weight is similar to the realized genetic correlation between litter size and 6-week body weight of 0.52 * 0.10 (EISEN 1978).

The phenotypic correlation between testis weight and body weight in the pres- ent study (rpTw= 0.30 f 0.09) is similar to the phenotypic correlation between litter size and body weight [rpLrv = 0.27 t- 0.03 (EISEN 19781, and both pheno- typic correlations were lower than the corresponding genetic correlations. An explanation for the low phenotypic correlations and high genetic correlations is the relatively small environmental correlations (IETJv, ?-ELw ) , which can be veri- fied by writing the phenotypic correlation as (FALCONER 1960)

T p T I V = h w h ~ r G ~ ~ + (1-hh2,)s (l-h",)'/rETW,

assuming no nonadditive genetic effects. Solving for the environmental correla- tion gives r E T w = 0.03, and similarly rELw= 0.19. The conclusion reached from these low environmental correlations is that micro-environmental and nongenetic developmental effects contribute little to the relationship between testis weight and body weight or litter size and body weight. Alternatively, since the expecta- tions of rgTW and ?-ELW include nonadditive genetic correlations, the combined effects of environmental correlations and nonadditive genetic correlations are small.

The realized partial genetic correlation between testis weight and litter size, holding body weight constant, can now be computed by substituting the estimates of the realized ordinary genetic correlations into

" T L - rGTW l G L W

which equals 0.42. The magnitude of the partial genetic correlation indicates that pleitropic gene loci controlling reproductive processes affect testis weight and litter size independently of body weight. The assumption is made, when calculat- ing the partial genetic correlation, that the genes affecting litter size and testis weight through reproductive processes are independent of the genes affecting litter size and testis weight allometrically through body weight. Provided that this assumption is valid, the genetic correlation between testis weight and litter size can be partitioned as rGTt = k + rGTW rGLw (LI 1955), where k is the product of the genetic correlation between testis weight and reproductive function aEd the genetic correlation between litter size and reproductive function. Substituting the estimates of rGTW and rGLW into the above equation for rGII,L and solving for k gives 0.29 and k/rGTr, = 0.48. Therefore, approximately one-half of the realized genetic correlation between testis weight and litter size can be explained by the common causal effects of genes controlling reproductive function, the other half being due to the common causal effects of genes controlling body weight.

The realized genetic correlations were based on lines selected for plus genes for litter size, testis weight or body weight. Single-trait selection for a reduction in each of these traits was not conducted, so that no check was possible for symmetry of the genetic correlations.

522 E. J . EISEN A N D B. H. J O H N S O N

The hypothalamic-pituitary-testicular axis is subject to genetic variation (SHIRE 1978). However, there is a paucity of information regarding genetic con- trol of this axis. It has not been determined whether genes influence reproductive processes by altering such steps as rate of synthesis and/or secretion of hypo- thalamic releasing hormones and pituitary gonadotrophins, catabolism and meta- bolic clearance rates of hormones, sensitivity of gonadal tissue to gonadotrophins, or by combination of these and other mechanisms.

Testis weight increased in both L+W- and L-W+ males, illustrating an ex- treme form of asymmetrical response. The asymmetry cannot be explained by differences between the index selected lines in the absolute values of the selection intensity of the index o r the index weights for body weight and litter size (EISEN 1978). Genetic drift is not a likely explanation either because of the large effec- tive population sizes used in the index lines, although it cannot be completely excluded. BOHREN, HILL and ROBERTSON (1966) used a deterministic model to demonstrate that asymmetrical correlated responses may be expected on the basis of gene frequency changes more often than not.

The predicted response in testis weight due to selection in the L+W- line for the index I = bl+.PrV + bLPL is

where t = number of generations of selection, i = selection intensity, = stand- ard deviation of the index, and bw and bL are the index weights of the phenotypes for body weight (Plv) and litter size ( P L ) . Since the realized estimates of rGTW and rGTL both equal 0.60 and the ratio of realized index weights (bw/bL) = - 0.8, AGT.1 > 0 if hL up,, - 0.8 h,, u p , > 0. Using realized heritabilities and base popu- lation phenotypic standard deviatiom, aGT.1 is negative, but using estimates of up, and upTV from generation 22 gave a positive AGT.r. The same argument holds vis-& vis in the L-W+ line. Therefore, the predicted response is equivocal.

An explanation for the asymmetrical correlated response in testis weight in the index lines is proposed by considering that the realized genetic correlation between testis weight and litter size has two possible causes. Recall that the com- mon causes of body weight and reproductive function appear to contribute equally to the genetic correlation. It is feasible, therefore, that the positive correlated re- sponses in testis, seminal vesicle and epididymis weight in the L+W- line were due primarily to positive changes in genes controlling reproductive processes. On the other hand, the positive change in testis weight in the L-W+ line could have been the result of changes in the genes associated with body weight. Evidence to support this hypothesis can be seen by comparing testis growth relative to overall body growth in the period of rapid development from 4 to 8 weeks of age. Testis size increased more rapidly in LfW- as compared to the K and L-W+ mice. Con- sequently, the rate of testis growth relative to body growth during the period of sexual development is markedly higher in L+W- as compared to L-W+ males.

The correlated responses in epididymis and seminal vesicle weight in each line follow a pattern similar to that observed for testis weight, and we have to assume

CORRELATED RESPONSES IN M I C E 523

for now that the same genetic changes are responsible. The adrenal gland was not affected by the selection criteria.

The failure to demonstrate differences in serum concentrations of testosterone may be attributed to the large variation among individuals within lines. Evaluat- ing differences in the capacity of Leydig cells of individual mice to synthesize and secrete testosterone is extremely difficult because of the complex regulatory systems that control testicular steroidogenesis. For example, episodic increments in circulating testosterone titers begin to occur during sexual maturation and, in the adult male, pulsatile release of pituitary LH results in a transient increase in secretion rate of testosterone, which is dictated partly by environmental cues (DESJARDINS 1981). The concept of LH-induced Leydig cell steroidogenic de- sensitization (HSUEH, DUFAU and CATT 1976; TSURUHARA et al. 1977) alzd the discovery of different populations of Leydig cells that can respond differently to LH (PAYNE, WONG and VEGA 1980) further enhance the complex nature of the hypothalamic-pituitary-testicular axis. Thus, the procedure of using only one estimate of peripheral concentration of testosterone to evaluate the capacity of Leydig cells to synthesize and secrete testosterone is inadequate for measuring relatively small differences. It is likely, however, that large differences in serum concentrations of testosterone can be adequately evaluated from one blood sample. The inherent problems in collecting sequential blood samples from large numbers of mice over long periods of time dictate that this approach be used.

LITERATURE CITED

BOHRLN, B. B., W. G. HILL and A. ROBERTSON, 1966

CUNNINGHAM, P. J., M. E. ENGLAND, L. D. YOUNG and D. R. ZIMMERMAN, 1979

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Corresponding editor: B. S. WEIR

PROUD, C., D. DONOVAN, R. KINSEY, P. J. CUNNINGHAM and D. R. ZIMMERMAN, 1976