0163-769X/91/1201-0078$03.00/0 Endocrine Reviews Copyright © 1991 by The Endocrine Society

Vol. 12, No. 1 Printed in U.S.A.

The Major Histocompatibility Complex and Reproductive Functions* S. P. LERNER AND C. E. FINCHf Division of Animal and Veterinary Sciences, West Virginia University, Morgantown, West Virginia 265066108; and Andrus Gerontology Center and Department of Biological Sciences, University of Southern California, Los Angeles, California 90089-0191

I. Introduction

that exert a major influence on histocompatibility. Chordates show a remarkable similarity in the organization and types of genes that are present in their respective Mhcs. This may not be apparent at first, because the Mhc has a different name in each species and occurs in a differently numbered chromosome (Fig. 1). The evolutionary stability of the linkage of particular genes (synteny) is not unique to the Mhc, e.g. more than half of the linkage groups characterized in Xenopus show some synteny with human gene maps (7). Mhc class I and class II genes encode membrane glycoproteins (8); for a detailed review of the structure, function, and diversity of class I molecules, see Ref. 9. Class I antigens are expressed ubiquitously throughout the body and are the main basis for graft rejection but also have a major role in presentation of exogenous and endogenous antigens. Certain alleles of class I antigens are associated with increased risk of particular diseases that include the classic example of ankylosing spondylitis (10, 11). In contrast to class I antigens, class II antigens occur mostly on bone marrow-derived cells, including B cells, activated T cells, macrophages, and other antigenpresenting cells. The number of exons and the polypeptide domain characteristics are similar for genes within each class. These molecules share certain sequence and structural similarities with other members of the immunoglobulin superfamily (5,12). In addition to their role as transplantation antigens, Mhc glycoproteins serve a major role in antigen presentation, and their presence on the cell-surface can influence hormone responses. The receptors for foreign antigens on cytotoxic T cells require that class I glycoproteins also be present at the surface of the antigen-presenting cell. In contrast, helper T cells require a class II glycoprotein to be present with the foreign antigen. In each case, particular Mhc alleles determine the qualitative or quantitative nature of the immune response to a given antigen. This property of T cells is referred to as Mhc restriction, since the immune response is restricted to

T

HIS review summarizes a scattered literature on genotypic influences on reproductive functions that have been associated with the major histocompatibility complex, the Mhc. While much attention has been given to the roles of the Mhc in immunological functions and disease resistance (1, 2), abundant evidence shows that Mhc-associated genes also influence numerous hormonally related functions. In particular, Mhc polymorphisms are associated with quantitative variations in diverse reproductive traits. These findings are discussed in relation to other genetic studies on reproductive functions. The forthcoming knowledge of nucleotide sequences of Mhc genes and non-class I and class II genes within the Mhc, e.g. in mice (3) and in cows (4), should open important opportunities to study reproductive mechanisms at the molecular level and to create genetically engineered animals for testing of experimental hypotheses and for meeting human needs. We also discuss genotypic influences on reproduction in relation to natural selection for the reproductive schedule. II. Overview of the Mhc

All vertebrates examined have a sizable cluster of genes in their Mhc that contains polymorphic loci governing histocompatibility (1, 2, 5, 6). Mhc genes were first identified as loci that coded for histocompatibility or transplantation antigens. Although histocompatibility genes have been mapped on several chromosomes, the Mhc contains the largest assembly of closely linked loci Address requests for reprints to: S. P. Lerner, Division of Animal and Veterinary Sciences, West Virginia University, Morgantown, West Virginia 26506-6108. * Published with the approval of the Director of the West Virginia Agriculture and Forestry Experiment Station as scientific paper No. 2243. t Present address: Andrus Gerontology Center and Department of Biological Sciences, University of Southern California, Los Angeles, California 90089-0191.

78

The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 13 November 2015. at 04:42 For personal use only. No other uses without permission. . All rights reserved.

February, 1991

THE Mhc AND REPRODUCTION

79

DY DO DO DR

Bovine

4HF

BoLA

23

DO? Off

Equine

II

ELA

nun DP

FIG. 1. Genetic map of class I and class II loci in different species. Open rectangles are class I genes; closed rectangles are class II genes; the hatched rectangle in chickens indicates the B-G antigen (see text). The maps show current status as determined by formal genetics methods. Homologies as indicated by the position represent the interpretation of J. Klein. Redrawn from J. Klein: The Natural History of the Major Histocompatibility Complex, John Wiley & Sons, New York, 1986 (1); 'R. Fries et al.: Anim Genet 17:287, 1986 and 2H. A. Ansari et al.: Immunogenetics 28:362, 1988]

Human

Mouse

HLA

DO

DR

K

A

B C

E

D M L

Oa-2

Tla

H-2

17

A

Rat

20

B

D

RT1

14

DO DR

Swine

SLA

Chicken

B

Xenopus XLA

cells that present both an antigen and a particular Mhc allelomorph. The influence of class I glycoproteins on hormone responses in mice, as discussed below, implies ancient molecular relationships between Mhc glycoproteins and responses to a variety of proteinaceous signals. The class I and II glycoproteins also show a remarkable extent of polymorphism in human populations, such that there are 30-60 alleles (allelomorphs) of each class I gene, and, in general, slightly fewer alleles of each class II gene. Unlike the more limited set of polymorphisms in other Mhc genes which generally show a few prevalent alleles, the multiple alleles of class I and II genes occur throughout human populations and rarely exceed a frequency of 10% (1). Of the 25 million or so possible combinations of alleles in humans, a much smaller number has been found, and many of these allelic combinations show extensive linkage disequilibrium, i.e. particular combinations of alleles occur in much higher fre-

II LGX

II quency than predicted from random combinations. While wild mice appear to have extensive Mhc polymorphisms particularly in class I glycoproteins (1, 13-16), some other mammals may have markedly fewer Mhc polymorphisms (1, 17). The importance of Mhc polymorphisms in favoring survival of the genes encoding resistance to disease in human populations is an ongoing debate (1, 18). The extent of Mhc polymorphisms in natural populations is pertinent to a later discussion on the role of Mhc alleles as genetic substrates for selection of reproductive schedules. In addition to the class I and II genes, the Mhc contains genes coding for several serum complement factors (class III genes). Throughout the Mhc there are genes with no obvious role in immune function; steroid 21-hydroxylase (a P450 enzyme); complement factor 4 (C4; also known as Sip, or sex-limited protein); mixed function oxidases that are important in detoxification; heat shock protein

The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 13 November 2015. at 04:42 For personal use only. No other uses without permission. . All rights reserved.

LERNER AND FINCH

80

A/WySn (A) mouse strains have haplotypes designated H-2h and H-2a, respectively. The B10.A congenic strain was then created by crossing the B10 and A inbred strains, followed by extensive backcrossing of the Fx to B10 mice. After sufficient backcrossing with selection for recombinants that contain the H-2a haplotype, a lineage can be found in which the mice are homozygous for the H-2 region from the A strain, while most of the rest of chromosome 17 and virtually all other chromosomes come from the B10 strain. The resulting B10.A strain is designated by the symbols of the two parental strains used in the initial cross, separated by a period. Through large-scale immunogenetic studies throughout the world, there is now an inventory of hundreds of H-2 congenic strains and recombinants of these (1, 22). The boundaries of the DNA in recombinants are not precisely known in most cases, since recombination is determined using markers that do not exclude flanking or passenger DNA (23, 24).

(HSP-70); tumor necrosis factors a and 0; and others, as summarized for the murine H-2 complex (Fig. 2). Several loci that influence reproduction are near to, but outside the Mhc, including the T/t-locus of mice and the growthreproduction complex (Grc) of rats. The size of the Mhc is 1-10 centimorgans of chromosomal map distance, which approximates 1-20 million nucleotide pairs; for comparison, the Escherichia coli genome is ca. 4 million nucleotide pairs. While this could be enough DNA for 100 or more eukaryotic-sized genes, the Mhc also has unknown numbers of pseudogenes (19). There are extensive differences among species in the numbers of genes of each class and in the extent of their allelic diversity or polymorphism. Mouse strains even differ in the numbers of class I genes (Ref. 20). Most Mhc loci have typical rates of germ line mutation, although one locus in C57BL/6J mice, the / region, has a relatively high mutation rate (1, 21). Considerably more of the Mhc has been sequenced in mice and humans than in other species. Knowledge of the Mhc was historically based on inbred mouse strains that were used to identify transplantation antigens. Brother-sister mating can be used to create lines of mice; by convention, after 20 generations of such matings, individual lines are designated as new strains (1). An inbred strain is considered to be more than 99% genetically homogenous by theoretical calculations (1) and by the criterion of histocompatibility in transplantation studies. Strains of mice can be distinguished by H-2 haplotype, or particular set of H-2 genes. Histocompatibility congenic strains can be created by crossing inbred lines followed by backcrossing hybrids to one parental line while selecting for the H-2 haplotype of the other (22). For example, the C57BL/10Sn (B10) and centromere

III. Description of the Mhc Influences on Reproduction by Species This section reviews the association of Mhc variants with quantitative variations in reproductive functions. While most reports are phenomenological and present only empirical data, recent studies use the alleleic variation in Mhc glycoproteins to analyze physiological mechanisms in reproduction and hormone responses, just as is done on a huge scale in molecular immunology. Species are presented alphabetically; Table I summarizes these diverse findings. We emphasize that the demonstration of Mhc effects does not preclude distinct H-2 Tla

10 cM

Vol. 12, No. 1

pgk-2

C3

lr-5

t— 21-OH

•

,_ CO

;

B10.F (Fig. 4) (80). The B10.RIII

100 *. \ 80 -

\

mn DO DiU.DK

\

B10

V \ \

\

V \ V

8 60-

V

'

E

y \

•5 g?

\ \

\

•'•••

"••• \ \

40 -

\

'••--A \ \

V

V \

\V

\ \

20 -

\ \ V

N

n

60

120

180

240

300

360

420

Age (days)

FIG. 4. Percentage of mice that had litters us. advancing maternal age. Differences in the x-intercept (B10.F < BIO < B10.BR and B10.RIII) and the slope of each line (B10.F > BIO > B10.BR and B10.RIII) are indicative of the effects of strain and maternal age on fecundity. [Redrawn with permission from S. P. Lerner et al: Biol Reprod 38:1035, 1988 (66).]

The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 13 November 2015. at 04:42 For personal use only. No other uses without permission. . All rights reserved.

84

LERNER AND FINCH

B10.F (H-2P) strain is unusually short lived, and shows premature death in association with atypical graying and an early-onset murine leukemia from a xenotropic MuLV that is transmitted through maternal milk and is eliminated by cross-fostering (81). Among retired breeders of the congenic strains, the age at onset of acyclicity differed with strain and ranked with longevity; however, this effect was small in comparison to the difference between B6 and the other strains (66). B6 mice showed a 3-month earlier onset and more rapid increase of acyclicity with age than the BlO-congenic mice. This indicates a non-H-2 effect, since both B6 and BIO mice share the H-2b haplotype as noted above (65). Reproductive anatomy and function of the male. Weights of the testes and of the seminal vesicle were examined in inbred strains [A (H-2&), AKR (H-2k), and C57BL/10 (BIO; H-2h) and the congenic partner of the latter B10.A (#-2 a )], as well as in various hybrids [(A x BlO)F b (AKR x B1O)F1} (A x B10)F2, and (AKR x B1O)F2 males] (34, 82-84). These organ weights differed by as much as 48% among H-2 haplotypes, possibly in association with alleles of a gene influencing androgen metabolism (Hom1). F2 males (AKR x BIO and A X BIO) with the H-2hb haplotype had heavier seminal vesicles (+15%) and slightly smaller (-3%) testes than H-2m and H-2kk males. Plasma concentrations of testosterone and testosterone binding capacity differed with strain and with H-2 haplotype (82, 85). As might be expected from larger testes, males of the H-2a, H-2aa, and H-2ah haplotypes had higher serum testosterone than H-2h and H-2hh haplotypes. Interestingly, the difference in the weight of the seminal vesicles between the A and the BIO strain was at least in part attributable to a differential tissue sensitivity to testosterone (86). However, that difference was not related to H-2 haplotype, as shown by comparison of the BIO males with the congenic BIO.A recombinant; their sensitivity to testosterone did not differ, while difference in weights of the seminal vesicles persisted (87). Hormone receptors. Several laboratories have demonstrated a role for class I glycoproteins in peptide hormone receptor function (Refs. 88-90 and Fig. 5). Strain differences in glucagon-receptor binding affinities and subsequent adenylate cyclase activation were associated with differences in class I antigens. For example, carriers of k alleles have no detectable high affinity receptors for glucagon, although these animals are within the norm for fecundity (66) and lifespan (80). With regard to reproduction, LH receptors are integrally associated with class I antigens on the Leydig cells of the testes (91). We hypothesize that differences in binding affinities of LH receptors exist among congenic

Vol. 12, No. 1

strains of mice, particularly those that differ at the K and D regions of the H-2 complex. After artificial selection for a suite of reproductive and growth parameters, the resulting lines show differences in concentrations of high affinity LH binding sites but no difference in dissociation constant (Kd) (92-94). However, no assessments have been made of concentrations of low affinity sites. Differences in LH binding and/or adenylate cyclase activation at the gonads could affect subsequent steroid hormone production, thereby altering follicular development and corpora luteal lifespan and function in the female, and androgen production and spermatogenesis in the male. We also note that the transcription of class I genes is regulated by a nuclear hormone receptor that binds to an estrogen response element (95). Thus, H-2 genes are well integrated into physiological control systems that allow many pleiotropic effects. F. Rat growth-reproduction

complex (Grc)

In laboratory rats (Rattus norvegicus), the Grc and RT1 (rat Mhc) lie far enough apart to be easily separable by recombination (35); therefore that phenomena discussed below may be Mhc linked (separated by 0.6 centimorgans (cM) but are not strictly Mhc dependent. The Bl strain of rats carries a mutation that diminishes its growth and reproduction; adults of both genders are 20% smaller in size. Males are infertile with hypoplastic and aspermatic testes. Females are sufficiently fertile to perpetuate the strain directly, but not prolific (35,96). Backcrossing proved that the loci controlling these defects are linked to the RT1 complex. Genes governing these defects are designated the growth and reproduction complex (Grc); the recessive regulating small body size is designated dw-3 (dwarf-3); the recessive influencing reproductive capacity is designated f. Male reproductive anatomy and function. The effects of the Grc on reproduction were shown in F2 hybrids generated from BIL/1 females (RTf-Grc) and YO males [{RT1U-Grc+ (97)]. The RTl1 testes showed arrested spermatogenesis at the early pachytene stage of the primary spermatocytes and were 90% lighter than in the RT11/U and RTlu/u haplotypes. Further analysis of testicular morphology in Grc+ homozygotes showed the following (98): a loss of the normal organization in the tubular epithelium; arrest of spermatogenesis at pachytene in primary spermatocytes; cellular degeneration and necrosis; reduplication and invagination of the basal lamina into the seminiferous tubule; increased numbers of abnormal Sertoli cells, and increased interstitial fibrous tissue. Heterozygotes had similar, but more modest defects. These abnormalities have been linked to changes in enzyme activity within the testes. The activity of

The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 13 November 2015. at 04:42 For personal use only. No other uses without permission. . All rights reserved.

February, 1991

FIG. 5. Schematics showing the interaction of class I antigens and peptide hormone receptors. Panel A depicts a scenario in which peptide hormone receptors are capable of binding to class I glycoproteins at their j32-microglobinbinding site, thereby altering the hormone binding affinity of the receptor, possible via an allosteric action: /32-microglobulin exists in free and bound forms. Panel B depicts a scenario in which class I glycoproteins are incapable of interacting with peptide hormone receptors due to improper conformation.

THE Mhc AND REPRODUCTION

class I glycoprotein with bound 62-microglobin

85

„ cytosolic component

transmembrane . component

receptor bound to class I £ W n a t B2-microglobin binding site

glyoop

B

no interaction of class I glycoprotein with receptor

testicular germ-cell galactolipid sulfotransferase was elevated in Grc+ homozygotes with a concomitant deficiency of a developmentally regulated sulfotransferase inhibitor (99). Female reproductive anatomy and function. As noted above, females Grc+ homozygotes are fertile, but not prolific. Although there was no difference in ovarian weight in females of the RTll/\ RTll/u, and RTlu/u haplotypes, the RTlin homozygotes showed reduced rate of ovulation (75). This deficiency was associated with 10% fewer secondary ovarian follicles and a 25% increase in atretic follicles, which indicates abnormal development of primary follicles (96). Thus, the genetic defect in gametogenesis controlled by the Grc appears to occur at the same stage of gametogenesis in both males and females. G. Swine lymphocyte antigen (SLA) complex Domestic swine {Sus scrofa) show differences due to breed for many reproductive variables, including age at puberty and continuation of normal estrous cycles (100, 101), rate of ovulation (102-104), and litter size (105). Associations between SLA haplotype and reproduction have been studied as extensively in swine as in laboratory mice (106-108). In males, SLA haplotypes influence differential genital tract development; including development of the testes, the epididymis, and the Cowper's glands [reduced in haplotype H4 vs. H15 and H16 (36)]. Females show no evidence for an influence of SLA haplotype on reproductive tract anatomy. However, SLA

haplotypes are associated with differences in factors that affect fertility and fecundity. Rate of ovulation. Artificial selection of sows for high rates of ovulation shift the distribution of SLA haplotypes (109): after nine generations, the H10 haplotype increased in frequency at the expense of the H4 haplotype. In support of this observation, sows of the LargeWhite breed that were homozygous for the H10 haplotype had approximately 40% more ovulations than sows homozygous for the H4 haplotype or heterozygous for the H10 haplotype (106). Lastly, among inbred lines of miniature swine, females homozygotes for the SLAd haplotype had an average of two and three more ovulations than did homozygotes for the SLAa or SLAC haplotypes, respectively (110). Fertility and fecundity. Aside from rates of ovulation and fertilization, there is evidence for influences of the SLA on embryonic mortality as assessed by size of the litter at birth and by segregation distortion of offspring (108,111-113). In an analysis of 58 litters, both maternal and paternal haplotype affected the size of litters (over a 2- to 3-fold range) among a variety of SLA combinations (113). In contrast, for the Large-White breed of pigs, litter size at birth was only marginally affected by the SLA complex (as reviewed in Ref. 106); indicative of possible breed-Mhc interactions. Among inbred lines of miniature swine, litters from sows that were homo- or heterozygous for the d haplotype or from boars homozygous for the d haplotype were larger by two to three piglets compared to all other matings (110). Although ovulation rate was higher in homozygous

The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 13 November 2015. at 04:42 For personal use only. No other uses without permission. . All rights reserved.

LERNER AND FINCH

86

d sows (see above), the effect of sire SLA genotype on size of the litter is evidence for an additional effect of the d haplotype on embryonic survival.

IV. Future Questions Several major questions are raised by these findings. First, the ubiquitous expression of class I glycoproteins and their interaction with multiple families of peptide hormone receptors, e.g. receptors for insulin, glucagon, epidermal growth factor, and LH, leads to the hypothesis that allelic variants of class I glycoproteins have pleiotropic effects that are distinct from immune function. Of interest is the effect of allelic variants of a class I glycoprotein expressed by preimplantation mouse embryos [Qa-2 antigen (114)] on embryonic growth and subsequent survival. The physiological basis for the differential action of allelic variants of the Qa-2 antigen is unknown and could involve an altered reception of intrauterine hormonal signals by the embryo. In view of the numerous associations of Mhc variants with quantitative differences in wide ranging physiological functions, we suggest that the existence of extensive Mhc polymorphisms in natural populations of humans and some other mammals (1, 3-16) implies that diverse functions influencing fitness in the evolutionary sense are influenced by selection for particular sets or haplotypes of Mhc alleles. Mhc influences on behavioral and neuroendocrine functions are indicated, again in laboratory mice, but their molecular basis is not known. According to classical arguments, these pleiotropic effects of alleles can account for the evolutionary persistence of the Mhc organization and the linkage disequilibrium associated with particular combinations of alleles, which allows the aggregation of advantageous allelic sets because of the low frequency of recombination within closely linked gene sets. In due course, we may be able to discuss the characteristics of various Mhc reproduction haplotypes. We also note that the pertinence of genetic polymorphisms in the Mhc to questions in evolutionary biology are not usually discussed during presentations of reproductive phenomena to research communities that focus on the physiology and molecular biology of gnotobiotic laboratory animal models. The Mhc-associated variations in reproductive functions can be regarded as the basis for selecting for optimum reproductive schedules in a population that is exposed to fluctuating environmental influences. Species and even populations can be distinguished by quantitatively varying reproductive functions that include age at first reproduction, interval between ovulations, interval between births, and the duration of fecundity. A major literature in evolutionary biology addresses selection of genotypes on the basis of

Vol. 12, No. 1

trade-offs in mortality at various stages in life history against the total reproductive potential of a given genotype (115-123). The act of reproduction itself may increase mortality ("reproductive costs") (121, 122), depending in part on metabolic stores (e.g. Ref. 123). If adult mortality is high, e.g. because of vulnerability to predators or infectious organisms, there may be selection for genotypes with more offspring per clutch and shorter generation times with earlier maturation ("r-selection"). Conversely, low mortality rates may favor selection of genotypes with delayed maturation and fewer conceptuses and longer adult phases ("K-selection"). In addition to influence from Mhc alleles on reproduction per se, the Mhc complex contains two other major categories of loci that in theory are germane to the selection of the fittest genotypes. The influence of class I glycoproteins on the cAMP generation in response to occupancy of insulin and glucagon receptors as shown in mice (see above, Refs. 88-90) could influence metabolic reserves that are often major determinants of the onset of puberty and the capacity for sustaining reproduction during fluctuations in food supply. Thus the Mhc could influence reproductive costs through variants that control metabolic reserves. So far, the H-2 influences on insulin and glucagon receptors have not been studied in relation to effects on reproduction during dietary insufficiency. A further link of the Mhc to local features of the environment could involve Mhc restriction (see Section II), through which particular class II glycoproteins determine the efficacy of immune responses to particular antigens, which could include those on viral and parasitic pathogens. Thus, the Mhc has the potential, through accumulated polymorphisms, to provide genetic variants that can be readily selected for on the basis of reproductive schedules, metabolic reserves, and resistance to pathogens in response to environmental fluctuations. In closing, we note recent studies that demonstrate the ability of naturally occurring genotypes to respond to selection on this basis. So far, no such study has considered a vertebrate with defined Mhc. In Drosophila melanogaster, artificial selection has succeeded in delaying senescence on the basis of reproduction at late ages, with reversible alterations in the schedule of egg laying, such that the lines that delayed reproduction also lived longer (124-127). These studies utilized the naturally occurring genetic variants in outbred fly populations. Another example is the climatic fluctuations that shifted reproductive schedules in natural populations of Drosophila mercatorum. One genotype matured slightly earlier because of a complex molecular cascade beginning with an underreplication of ribosomal RNA genes during polytenization that causes deficiencies in juvenile hormone esterase and results in sustained levels of juvenile hormone; consequently ovarian development is precocious (128, 129).

The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 13 November 2015. at 04:42 For personal use only. No other uses without permission. . All rights reserved.

THE Mhc AND REPRODUCTION

February, 1991

Finally, natural populations of the guppy Poecilia reticulata were subject to selection of reproductive schedules by introducing natural, but size-specific predators (120), and showed heritable changes in reproductive schedules according to the model of r-selection. These examples illustrate the importance of existing genetic polymorphisms in response to experimental or natural selection and, when considered with the evidence assembled here, give a rationale for investigating the Mhc's potential role in selection for reproductive schedules in natural populations. Thus, we can view the Mhc influences on rates of ovulation, fetal death, rates of development, and age at last litter etc. as substrates for evolutionary selection in reproductive schedules as a major feature of life history variations (130). However, the Mhc variants that are described for the domestic and laboratory species can not be considered as resulting from natural selection. It would be of great interest to know how natural populations and species vary in the range of Mhc allelic variations that influence reproductive functions, and in the extent of linkage disequilibrium in these putative Mhc reproduction haplotypes. As the molecular basis for these genetic variants in reproductive functions becomes known under laboratory conditions, we may then have a powerful battery of probes for studying field populations of these and related species. Recombinant genetics through polymerase chain reaction techniques now allow rapid characterization of allelic variants from field populations at the level of the DNA sequence. V. Conclusions Genetic variants in the Mhc might have many quantitative influences on reproductive functions, as shown by post hoc analysis of laboratory inbreed and artificial selection for reproductive traits. The unexpected feature is the recognition that murine Mhc haplotypes acting through class I molecules have such strong effects on hormone receptor functions in tissues governing reproduction and metabolism. Mhc class II glycoproteins also are subject to selection from viral and other antigens in the natural environment through the phenomena of Mhc restriction that influence the efficacy of immune responses. Thus, there are rich prospects for molecular analyses of variations in hormone effects that may underlie between and within species differences in physiological functions.

References 1. Klein J 1986 The Natural History of the Major Histocompatibility Complex. John Wiley & Sons, New York 2. Warner CM, Rothschild MF, Lamont SJ (eds) 1987 The Molecular Biology of the Major Histocompatibility Complex of Domestic Animal Species. Iowa State University Press, Ames, IA

87

3. Kuhner MK, Goodenow RS 1989 DNA sequences of mouse H-2 and Qa genes. Immunogenetics 30:458 4. Groenen MAM, van der Poel J, Dijkhof RJM, Giphart MJ 1990 The nucleotide sequence of bovine MHC class II DQG and DRB genes. Immunogenetics 31:37 5. Williams AF, Barclay AN 1988 The immunoglobin superfamily: domains for cell surface recognition. Annu Rev Immunol 6:381 6. Lew AM, Lillehoj EP, Cowan EP, Malloy WL, Van Schravendijk MR, Coligan JE 1986 Class I genes and molecules: an update. Immunology 57:3 7. Graf J-D 1989 Genetic mapping in Xenopus laeuis: eight linkage groups established. Genetics 123:189 8. Flavell RA, Allen H, Burkly LC, Sherman DH, Waneck GL, Wider G 1986 Molecular biology of the H-2 histocompatibility complex. Science 233:437 9. Bjorkman PJ, Parham P 1990 Structure, function, and diversity of class I major histocompatibility complex molecules. Annu Rev Biochem 59:253 10. Suarez-Almazor ME, Russel AS, LeClercq S 1986 Ankylosing spondylitis in families with two distinct B27 haplotypes: a selective association. Arthritis Rheum 29:1510 11. Ahearn JM, Calomiris JJ, Wigley FM, Jabs DA, Bias WB, Hochberg MC 1989 Characterization of the class I HLA 9.2-kb PVU II restriction fragment length polymorphism: linkage to HLA-A and lack of disease association. Arthritis Rheum 32:870 12. Bjorkman PJ, Saper MA, Samraoui B, Bennett WS, Strominger JL, Wiley DC 1987 Structure of the human class I histocompatibility antigen, HLA-A2. Nature 329:506 13. Figeroa F, Tichy H, Singleton G, Franguedakis-Tsolis, Klein J 1989 High frequency of H-2E° alleles among wild mice. Immunogenetics 30:222 14. Nobuhara H, Kuida K, Furutani M, Shiroishi T, Moriwaki K, Yanagi Y, Tada T 1989 Polymorphisms of T-cell receptor genes among wild laboratory and wild mice: diverse origins of laboratory mice. Immunogenetics 30:405 15. Orren A, Hayakaya J, Johnson JE, Nash HR, Hobart MJ 1988 Alotypes of mouse complement component C6 in inbred strains and some wild populations. Immunogenetics 28:153 16. Tine JA, Walsh A, Rathbun D, Leonard L, Wakefield EK, Dilwith R, Flaherty L 1990 Genetic polymorphisms of Q region genes from wild-derived mice: implications for Q regions evolution. Immunogenetics 31:315 17. Nizetic D, Stevanovic M, Soldatovic B, Savic I, Crkvenjakov R 1988 Limited polymorphism of both classes of Mhc genes in four different species of the Balkan mole rat. Immunogenetics 28:91 18. Robertson M 1982 The evolutionary past of the major histocompatibility complex and the future of cellular immunology. Nature 297:629 19. Steinmetz M, Winoto A, Minard K, Hood L 1982 Clusters of genes encoding mouse transplantation antigens. Cell 28:489 20. Stephan D, Sun H, Lindahl KF, Meyer E, Hammerling G, Hood L, Steinmetz M 1986 Organization and evolution of D region Class I genes in the mouse major histocompatibility complex. J Exp Med 163:1224 21. Steinmetz M, Stephan D, Lindahl KF 1986 Gene organization and recombinational hotspots in the murine major histocompatibility complex. Cell 44:895 22. Les EP 1980 Reproductive performance. In: Heiniger HJ, Dorey JJ (eds) Handbook on Genetically Standardized Jax Mice, ed 3. The Jackson Laboratory, Bar Harbor, ME, p 2.17 23. Klein D, Tewarson S, Figueroa F, Klein J 1982 The nominal length of the differential segment in H-2 congenic lines. Immunogenetics 16:319 24. Vincek V, Sertic J, Zaleska-Rutcynska Z, Figueroa F, Klein J 1990 Characterization of H-2 congenic strains using DNA markers. Immunogenetics 31:45 25. Bull RW, Lewin HA, Wu MC, Peterbaugh K, Antczak D, Bernoco D, Cwik S, Dam L, Davies C, Dawkins RL, Dufty JH, Gerlach J, Hines HC, Lazary S, Leibold W, Levezi'el H, Lie O, Lindberg PG, Meggiolaro D, Meyer E, Oliver R, Ross M, Simon M, Spooner RL, Stear MJ, Teale AJ, Templeton JW 1989 Joint report of the

The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 13 November 2015. at 04:42 For personal use only. No other uses without permission. . All rights reserved.

88

26.

27.

28. 29. 30.

31. 32. 33. 34.

35. 36.

37. 38. 39. 40.

41. 42. 43. 44. 45. 46. 47.

LERNER AND FINCH Third International Bovine Lymphocyte Antigen (BoLA) Workshop. Anim Genet 20:109 Andersson L, Bohme J, Rask L, Peterson PA 1986 Genomic hybridization of bovine class II major histocompatibility genes. I. Extensive polymorphism of DQa and DQ/3 genes. Anim Genet 17:95 Andersson L, Bohme J, Peterson PA, Rask L 1986 Genomic hybridization of bovine class II major histocompatibility genes. II. Polymorphism of DR genes and linkage disequilibrium in the DQ-DR region. Anim Genet 17:295 Sigurdardottir S, Lunden A, Andersson L 1988 Restriction fragment length polymorphism of DQ and DR class II genes of the bovine major histocompatibility complex. Anim Genet 19:133 Stear MJ, Pokorny TS, Echternkamp SE, Lunstra DD 1989 The influence of the BoLA-A locus on reproductive traits in cattle. J Immunogenet 16:77 Lunstra DD, Ford JJ, Echternkamp SE 1978 Puberty in beef bulls: hormone concentrations, growth, testicular development, sperm production and sexual aggressiveness in bulls of different breeds. J Anim Sci 46:1054 Blockley MA 1980 Getting the most out of rams, bulls and boars. Proc Aust Soc Anim Prod 13:46 Lunstra DD, Laster DB 1982 Influence of single-sire and multiple sire natural mating on pregnancy rate of beef heifers. Theriogenology 18:373 Batra TR, Lee AJ, Gavora JS, Stear MJ 1989 Class I alleles of the bovine major histocompatibility system and their association with economic traits. J Dairy Sci 72:2115 Ivanyi P, Gregorova S, Mickova M 1972 Genetic differences in thymus, lymph node, testes and vesicular gland weights among inbred mouse strains. Association with the major histocompatibility (H-2) system. Folia Biol (Praha) 18:81 Gill III TJ, Kunz HW 1979 Gene complex controlling growth and fertility linked to the major histocompatibility complex in the rat. Am J Pathol 96:185 Rothschild MF, Renard C, Sellier P, Bonneau M, Vaiman M 1986 Swine lymphocyte antigen (SLA) haplotype effects on male genital tract development and androsterone level. In: Dickerson GE, Johnson RK (eds) Proceedings of the Third World Congress on Genetics Applied to Livestock Production. University Press, Lincoln, NE, vol 11:197 Briles WE, Allen CP, Millen TW 1957 The B blood group system of chickens. I. Heterozygosity in closed populations. Genetics 42:631 Gilmour DG 1959 Segregation of genes determining red cell antigens at high levels of inbreeding in chickens. Genetics 44:14 Gilmour DG 1962 Current status of blood groups in chickens. Ann NY Acad Sci 97:166 Briles WE, Bumstead N, Ewert DL, Gilmour DG, Gogusev J, Hala K, Kock C, Longenecker BM, Nordskog AW, Pink JRL, Schierman LW, Simonsen M, Toivanen A, Toivanen P, Vainio O, Wick G 1982 Nomenclature for chicken major histocompatibility (B) complex. Immunogenetics 15:441 Briles WE, Briles RW 1987 Genetics and classification of major histocompatibility complex antigens of the chicken. Poult Sci 66:776 Simonsen M, Crone M, Koch C, Hala K 1981 The MHC haplotypes of the chicken. Immunogenetics 16:513 Briles WE 1954 Evidence for overdominance of the B blood group alleles in the chicken. Genetics 39:961 Briles WE, Krueger WF 1955 The effect of parental B blood group genotypes on hatchability and livability in Leghorn inbred lines. Poult Sci 34:1182 Briles WE, Allen CP 1961 The B blood group system of chickens. II. The effects of gentoype on livability and egg production in seven commercial inbred lines. Genetics 46:1273 Briles WE, Johnson LW, Garber MJ 1953 The effect of heterozygosity at the blood group locus B on weights at 9 weeks of age in related inbred lines of White Leghorns. Poult Sci 32:890 Briles WE 1957 The effect of B blood group system on 10-week weight of chicks resulting from a cross between inbred lines. Poult Sci 36:1106

Vol. 12, No. 1

48. Simonsen M, Kolstad N, Edfors-Lilja I, Liljedahl LE, Srensen P 1982 Major histocompatibility genes in egg-laying hens. Am J Reprod Immunol 2:148 49. Lamont SJ, Hou YH, Young BM, Nordskog AW 1987 Research note: differences in major histocompatibility complex gene frequencies associated with feed efficiency and laying performance. Poult Sci 66:1064 50. Kim CD, Lamont SJ, Rothschild MF 1989 Associations of major histocompatibility complex haplotypes with body weight and egg production traits in Si White Leghorn chickens. Poult Sci 68:464 51. MacCluer JW, Bailey E, Weitkamp LR, Blangero J 1988 ELA and fertility in American Standardbred horses. Anim Genet 19:359 52. Park CA, Hines HC, Threlfall WR 1989 Equine lymphocyte antigens and reproduction in the Standardbred mare. Anim Genet 20:99 53. Bailey E 1986 Segregation distortion within the equine MHC; analogy to a mouse T/i-complex trait. Immunogenetics 24:225 54. Shin HS, Stavnezer J, Artz K, Bennett D 1982 Genetic structure and origin on t haplotypes of mice, analyzed with H-2 CDNA probes. Cell 29:969 55. Treloar AE, Boynton RE, Behn BG, Brown BW 1967 Variation of the human menstrual cycle through reproductive life. Int J Fertil 12:77 56. Spector TD, Oilier WER, Perry LA, Silman AJ 1988 Evidence for similarity in testosterone levels in haplotype identical brothers. Dis Markers 6:199 57. Gerencer M, Tajic M, Kerhin-Brkljacic V, Kastelan A 1982 An association between serum testosterone level and HLA phenotype. Immunol Lett 4:155 58. Oilier W, Spector T, Silman A, Perry L, Ord J, Thomson W, Festenstein H 1989 Are certain HLA haplotypes responsible for low testosterone in males? Dis Markers 7:139 59. New MI 1985 Congenital adrenal hyperplasia. Ann NY Acad Sci 458:1 60. Gill III TJ 1983 Immunogenetics of spontaneous abortion in humans. Transplantation 35:1 61. Coulam CB, Moore SB, O'Fallon WM 1987 Association between major histocompatibility antigen and reproductive performance. Am J Reprod Immunol Microbiol 14:54 62. Christiansen OB, Riisom K, Lauritsen JG, Grunnet N 1989 No increased histocompatibility antigen-sharing in couples with idiopathic habitual abortions. Hum Reprod 4:160 63. Yamazaki K, Boyse EA, Mike V, Thaler HT, Mathieson BJ, Abbott J, Boyse Z, Zayas A, Thomas L 1976 Control of mating preferences in mice by genes in the major histocompatibility complex. J Exp Med 144:1324 64. Yamazaki K, Yamaguchi M, Baranoski L, Bard J, Boyse EA, Thomas L 1979 Recognition among mice. Evidence from the use of a Y-maze differentially scented by congenic mice of different major histocompatibility types. J Exp Med 150:755 65. Deleted in proof 66. Lerner SP, Anderson CP, Walford RL, Finch CE 1988 Genotypic influences on reproductive aging of inbred female mice: effects of H-2 and non-H-2 alleles. Biol Reprod 38:1035 67. Nelson JF, Felicio LS, Randall PK, Simms C, Finch CE 1982 A longitudinal study of estrous cyclicity in aging C57BL/6J mice. I. Cycle frequency, length, and vaginal cytology. Biol Reprod 27:327 68. Bindon BM, Pennycuik PR 1974 Differences in ovarian sensitivity of mice selected for fecundity. J Reprod Fertil 36:221 69. Barkley MS, Bradford GE 1981 Estrous cycle dynamics in different strains of mice. Proc Soc Exp Biol Med 167:70 70. Bradford GE 1969 Genetics control of ovulation rate and embryonic survival in mice. I. Response to selection. Genetics 58:283 71. Spearow JL 1986 Changes in the kinetics of follicular growth in response to selection for large litter size in mice. Biol Reprod 35:1175 72. Finch CE 1978 Genetic influences on female reproductive senescence in rodents. Birth Defects 14:335 73. Nelson JF, Felicio LS 1985 Reproductive aging in the female: an etiologic perspective. Rev Biol Res Aging 2:251 74. Goldbard SB, Verbanac KM, Warner CM 1982 Role of the H-2

The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 13 November 2015. at 04:42 For personal use only. No other uses without permission. . All rights reserved.

February, 1991

75. 76. 77. 78. 79.

80. 81. 82. 83. 84. 85. 86. 87. 88. 89. 90. 91.

92. 93.

94. 95.

96. 97.

THE Mhc AND REPRODUCTION

complex in preimplantation mouse embryo development. Biol Reprod 26:591 Goldbard SB, Verbanac KM, Warner CM 1982 Genetic analysis of H-2 linked gene(s) affecting early mouse embryo development. J Immunogenet 9:77 Goldbard SB, Warner CM 1982 Genes affect the timing of early mouse embryo development. Biol Reprod 27:419 Warner CM 1986 Genetic manipulation of the major histocompatibility complex. J Anim Sci 63:279 Warner CM, Gollnick SO, Goldbard SB 1987 Linkage of the preimplantation-embryo-development (Ped) gene to the mouse major histocompatibility complex (MHC). Biol Reprod 36:606 Warner CM, Gollnick SO, Goldbard SB 1987 Analysis of Qa-2 antigen expression by preimplantation mouse embryos: possible relationship to the preimplantation-embryo development (Ped) gene product. Biol Reprod 36:611 Smith GS, Walford RL 1977 Influence of the main histocompatibility complex on ageing in mice. Nature 270:727 Morse HC, Yetter RA, Stimpfling JH, Pitts OM, Frederickson TN, Hartley JW 1985 Greying with age in mice: relation to expression of murine leukemia virus. Cell 41:439 Ivanyi P, Forejt J, Gregorova S, Mickova M 1973 Reproductive performance and histocompatibility antigens. Haematologia (Budap) 7:185 Ivanyi P, Gregorova S, Mickova M, Hampl R, Starka L 1973 Genetic association between a histocompatibility gene (H-2) and androgen metabolism in mice. Transplant Proc 5:189 Gregorova S, Ivanyi P 1976 H-2 associated differences in the weight of some androgen influenced organs in (C57BL/10ScSnPh x AKR/J) F2 individuals. Folia Biol (Praha) 22:82 Ivanyi P, Hampl R, Starka L, Mickova M 1972 Genetic association between H-2 gene and testosterone metabolism in mice. Nature 238:280 Gregorova S, Ivanyi P 1973 H-2 associated genetic differences in androgen-dependent traits the effect of testosterone injections. Folia Biol (Praha) 19:337 Mickova M, Ivanyi P 1975 Influence of the H-2 system on the sensitivity of vesicular glands to testosterone hormone. Folia Biol (Praha) 21:435 LaFuse W, Edidin M 1980 Influence of the mouse major histocompatibility complex, H-2, on liver adenylate cyclase activity and on glucagon binding to liver cell membranes. Biochemistry 19:49 Phillips ML, Moule ML, Delovitch TL, Yip CC 1986 Class I histocompatibility antigens and insulin receptors: evidence for interactions. Proc Natl Acad Sci USA 83:3474 Verland S, Simonsen M, Gammeltoft S, Allen H, Flavell RA, Olsson L 1989 Specific molecular interaction between the insulin receptor and a D product of the MHC class 1. J Immunol 143:945 Solano AR, Sanchez ML, Sardanons ML, Dada L, Podesta EJ 1988 Luteinizing hormone triggers a molecular association between its receptor and the major histocompatibility complex class I antigen to produce cell activation. Endocrinology 122:2080 Spearow JL, Bradford GE 1983 Genetic variation in spontaneous ovulation rate and LH receptor induction in mice. J Reprod Fertil 69:529 Stavley JRD, Payne AH 1983 Luteinizing hormone receptors and testosterone production in whole testes and purified Leydig cells from mouse: differences among inbred strains. Endocrinology 112:1696 DeLeon DD, Zelinski-Wooten MB, Barkley MS 1990 Hormonal basis of variation in oestrous cyclicity in selected strains of mice. J Reprod Fertil 89:117 Hamada K, Gleason SL, Levi B-Z, Hirschfeld S, Appella E, Ozato K 1989 H-2RIIBP, a member of the nuclear hormone receptor superfamily that binds to both the regulatory element of major histocompatibility class I genes and the estrogen response element. Proc Natl Acad Sci USA 86:8289 Geyer SJ, Gill III TJ, Kunz HW 1983 Ovarian defect in rats carrying the growth and reproduction complex. J Immunogenet 10:55 Kunz HW, Gill III TJ, Dixon BD, Taylor FH, Greiner DL 1980 Growth and reproduction complex in the rat. Genes linked to the

98. 99.

100. 101. 102.

103.

104. 105. 106.

107. 108. 109. 110. 111. 112. 113. 114.

115. 116. 117. 118. 119.

89

major histocompatibility complex that affect development. J Exp Med 152:1506 Siew S, Gill III TJ, Kunz HW 1986 Ultrastructural investigation of the testicular defect in rats carrying MHC-linked genes affecting development (grc). Am J Pathol 123:318 Lingwood C, Kunz HW, Gill III TJ 1985 Deficiency in the regulation of testicular galactolipid sulphotransferase in rats carrying the growth-and-reproduction-complex (grc) gene. Biochem J 231:401 Zimmerman DR, Spies HG, Rigor EM, Self HL, Casida LE 1960 Effects of restricted feeding, crossbreeding and season of birth on age at puberty in swine. J Anim Sci 19:687 Christenson RK, Ford JJ 1979 Puberty and estrus in confinement reared gilts. J Anim Sci 49:743 Clark JR, Edey TN, First NL, Chapman AB, Casida LE 1973 Effects of four genetic groups and two levels of feeding on ovulation rate and follicular development in pubertal gilts. J Anim Sci 36:1164 Dailey RA, Clark JR, First NL, Chapman AB, Casida LE 1975 Effect of short-term "flushing" on follicular development at estrus and ovulation rate of gilts of different genetic groups. J Anim Sci 41:842 Young LC, Johnson RK, Omtvedt IT 1976 Reproductive performance of swine bred to produce purebred and two-breed cross litters. J Anim Sci 42:1133 Legault C 1986 Selection of breeds, strains and individuals for prolificacy. J Reprod Fertil 33:151 Vaiman M, Renard C, Bourgeaux N 1988 SLA, the major histocompatibility complex in swine: its influence on physiological and pathological traits. In: Warner CM, Rothschild MF, Lamont SJ (eds) The Molecular Biology of the Major Histocompatibility Complex of Domestic Animal Species. Iowa State University Press, Ames, IA, pp 23-38 Renard C, Vaiman M 1989 Possible relationships between SLA and porcine reproduction. Reprod Nutr Dev 29:569 Gautschi C, Gaillard C 1990 Influence of major histocompatibility complex on reproduction and production traits in swine. Anim Genet 21:161 Rothschild MF, Zimmerman DR, Johnson RK, Venier L, Warner CM 1984 SLA haplotype differences in lines of pigs which differ in ovulation rate. Anim Blood Groups Biochem Genet 15:155 Conley AJ, Jung YC, Schwartz NK, Warner CM, Rothschild MF, Ford SP 1988 Influence of SLA haplotype on ovulation rate and litter size in miniature pigs. J Reprod Fertil 82:595 Vaiman M, Renard C 1980 Deficit of piglets homozygous for the SLA histocompatibility complex in families. Anim Blood Group Biochem Genet 11:57 Gautschi C, Gaillard C, Schwander B, Lazary S 1986 Studies on possible associations between the MHC and reproduction traits in swine. Anim Genet 16:26 Mallard BA, Wilkie BN, Croy BA, Kennedy BW, Friendship R 1987 Influence of the swine major histocompatibility complex on reproductive traits in miniature swine. J Reprod Immunol 12:201 Warner CM, Gollnick SO, Flaherty L, Goldbard SB 1987 Analysis of Qa-2 antigen expression by preimplantation mouse embryos: possible relationship to the preimplantation-embryo-development (Ped) gene product. Biol Reprod 36:611 Williams GC 1966 Adaptations and Natural Selection. A Critique of Some Current Evolutionary Thought. Princeton University Press, Princeton, NJ Gadgil M, Bossert WH 1970 Life historical consequences of natural selection. Am Nat 104:1 Charlesworth B 1980 Evolution in Age-Structured Populations. Cambridge University Press, Cambridge, U.K. Sibly RM, Calow P 1982 Asexual reproduction in protozoa and invertebrates. J Theor Biol 96:401 Clutton-Brock TH, Alton SD, Guinness FE 1988 Reproductive success in male and female red deer. In: Clutton-Brock TH (ed) Reproductive Success: Studies of Individual Variation in Contrasting Breeding Systems. University of Chicago Press, Chicago, p325

The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 13 November 2015. at 04:42 For personal use only. No other uses without permission. . All rights reserved.

90

LERNER AND FINCH

120. Reznick DA, Bryga H, Endler JA 1990 Experimentally induced life-history evolution in a natural population. Nature 346:357 121. Bell G 1984 Measuring the cost of reproduction. II. The correlation structure of the life tables of 5 freshwater invertebrates. Evolution 38:314 122. Reznick D 1985 Costs of reproduction: an evaluation of the empirical evidence. Oikos 44:257 123. Reznick DN, Braum B 1987 Fat cycling in the mosquitofish (Gambusia affinis): fat storage as a reproductive adaptation. Oecologia (Berlin) 73:401 124. Rose MR 1984 Laboratory evolution of postponed senescence in Drosophila melanogaster. Evolution 38:1004 125. Rose MR 1990 Evolution of aging. In: Rothstein M (ed) Review of Biological Research in Aging. Allan Liss, New York, vol 4:3

Vol. 12, No. 1

126. Luckinbill LS, Arking R, Clare MJ, Cirocco WC, Buck SA 1984 Selection for delayed senescence in Drosophila melanogaster. Evolution 38:996 127. Arking R 1987 Successful selection for increased longevity in Drosophila: analysis of the survival data and presentation of a hypothesis on the genetic regulation of longevity. Exp Gerontol 22:199 128. Templeton AR, Rankin MA 1978 Genetic revolutions and control of insect populations. In: Richardson RH (ed) The Screwworm Problem. Univeristy of Texas Press, Austin, TX, p 81 129. Templeton AR, Hollocher H, Lawler S, Johnston JS 1989 Natural selection and ribosomal DNA in Drosophila. Genome 31:296 130. Finch CE, Longevity, Senescence, and the Genome. University of Chicago Press, Chicago, in press

Erratum In the article, "Development and Regulation of Growth and Differentiated Function in Human and Subhuman Primate Fetal Gonads," by Jaron Rabinovici and Robert B. Jaffe (Endocrine Reviews, 11:532557, 1990), the last sentence in the legend to Fig. 4, page 544, should read as follows: Reproduced with permission from F. I. Reyes, J. S. D. Winter, and C. Faiman, "Endocrinology of the Fetal Testis." In: H. Burger and D. de Kretzer (eds) The Testis. Raven Press, New York, 1989, p. 129.

The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 13 November 2015. at 04:42 For personal use only. No other uses without permission. . All rights reserved.