Primate spermatogenesis: new insights into comparative testicular organisation, spermatogenic efficiency and endocrine control

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Biol. Rev. (2005), 80, pp. 475–488. f 2005 Cambridge Philosophical Society doi:10.1017/S1464793105006755 Printed in the United Kingdom

Primate spermatogenesis: new insights into comparative testicular organisation, spermatogenic efficiency and endocrine control C. Marc Luetjens1, Gerhard F. Weinbauer2 and Joachim Wistuba1* 1 2

Institute of Reproductive Medicine of the University, Domagkstraße 11, D-48129 Mu¨nster, Germany Covance Laboratories GmbH, Kesselfeld 29, D-48163, Mu¨nster, Germany

(Received 12 February 2004; revised 21 January 2005 ; accepted 14 February 2005)

ABSTRACT Owing to the close phylogenetic relationship of Platyrrhini (New World monkeys) and Catarrhini (Old World monkeys) to man, nonhuman primates are often used as models for the study of male reproductive physiology and endocrinology. This review aims at providing new data and insights into comparative primate spermatogenesis, dealing specifically with quantitative aspects of germinal epithelial organisation and germ cell production, and with the roles of gonadotrophic hormones in this process. Typically, the seminiferous epithelium is composed of specific germ cell associations (spermatogenic stages). In rodents, prosimians and most Catarrhini, tubular cross sections contain a single spermatogenic stage whereas in Platyrrhini, great apes and man multi-stage tubules are present. Since Platyrrhini represent a more basal type of primate, this spermatogenic feature must have developed convergently. The primate multi-stage tubular arrangement was previously believed to be associated with low spermatogenic efficiency. However, recent studies using new methodological approaches and comparing primate species from all taxa have revealed that multistage organisation is compatible with highly efficient spermatogenesis. In fact, meta-analysis demonstrated that the efficiency of spermatogenesis in several nonhuman primate species is comparable to that of rodents which are considered as species with highly efficient germ cell production. The duration of the spermatogenic process was not related to organisation or efficiency of spermatogenesis. Sertoli cell work load was species-specific but had no impact on germ cell numbers and on the efficiency of spermatogenesis. The gonadotrophic hormones, luteinizing hormone (LH) and follicle stimulating hormone (FSH) are the primary regulators of primate testicular function. Recent studies revealed that in New World monkeys chorionic gonadotrophin (CG) – the primate pregnancy hormone – regulates testosterone production instead of LH. Receptor studies demonstrated a dual action of the closely related hormones LH and CG in primates. It is hypothesised that following the divergence of the Platyrrhini lineage from Catarrhini, the LH/CG system evolved independently with ancestral functions of the LH/CG system retained in the neotropical taxa. In summary, key spermatogenic features are preserved across all primate taxa whereas male reproductive endocrinology features appear substantially different in the neotropical primates compared to other primate lineages. Key words : primates, evolution, male reproduction, Sertoli cell work load, gonadotrophins. CONTENTS I. II. III. IV.

Introduction ................................................................................................................................................. Basic and specific features of spermatogenesis ........................................................................................ Organisation of the seminiferous epithelium ........................................................................................... Efficiency and duration of spermatogenesis .............................................................................................

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* Address for correspondence : Phone : ++49 251 83 56098, Fax : ++49 251 83 56093, E-mail : [email protected]

C. M. Luetjens, G. F. Weinbauer and J. Wistuba

476 V. VI. VII. VIII.

Endocrine control of spermatogenesis ...................................................................................................... Conclusions .................................................................................................................................................. Acknowledgements ...................................................................................................................................... References ....................................................................................................................................................

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Owing to their phylogenetic similarity to humans, nonhuman primates are of special interest for research in reproduction and serve as models for the development and regulation of the human male reproductive system. New World monkeys (Platyrrhini) and Old World monkeys (Catarrhini) have been used experimentally to elucidate and understand the mechanisms governing human reproductive physiology, endocrinology and male germ cell development (e.g. Clermont, 1972 ; Hearn et al., 1978 ; Preslock & Steinberger, 1978; Akhtar et al., 1982 ; Marshall, Wickings & Nieschlag, 1984; Pasqualini, Colillas & Rivarola, 1986; Rey et al., 1993 ; Weinbauer & Nieschlag, 1999 ; Millar et al., 2000; Black & Lane, 2002 ; Ginther et al., 2002 ; Peng et al., 2002; Narula et al., 2002) and spermatogenesis has been examined and described in detail for some primate species (e.g. Clermont & Leblond, 1959; Clermont & Antar, 1973; Chowdhury & Marshall, 1980 ; Dietrich, Schulze & Riemer, 1986; Smithwick, Young & Gould, 1996; Zhengwei et al., 1997; Weinbauer et al., 2001 a; Aslam et al., 2002). However, detailed and comprehensive knowledge about the physiology and endocrinology of spermatogenesis in nonhuman primates is limited to few species such as the cynomolgus monkey (Macaca fascicularis, Raffles, 1821), rhesus monkey (Macaca mulatta, Zimmermann, 1780) and to some extent to the common marmoset (Callithrix jacchus, Linnaeus, 1758). More recently, new comparative testicular data have become available for other nonhuman primates (Wistuba et al., 2003) and new quantitative approaches for studying male germ cell development, e.g. optical disector stereology and flow cytometry have been applied to testicular specimens from several primate species including man. Finally, molecular approaches have been used to compare primate reproductive endocrinology. These efforts have yielded some unexpected and surprising findings and challenge our current understanding of comparative primate spermatogenesis and endocrine control of testicular functions. It is the purpose of this review to focus on these new developments and highlight the ensuing general implications for testicular physiology and biology. Specifically, this review on comparative primate spermatogenesis deals with quantitative aspects of germinal epithelial organisation and germ cell production and with the roles of gonadotrophic hormones in this process.

the multiplication and proliferation of spermatogonial stem cells, recombination of genetic material during meiotic division of spermatocytes and differentiation and maturation of spermatids into testicular sperm (for review see Sharpe, 1994). However, species-specific differences are apparent with regard to the organisation of the germinal epithelium between primates and rodents (Clermont, 1963 ; Heller & Clermont, 1964; Alastalo et al., 1998) and among primates (Weinbauer et al., 2001a ; Aslam et al., 2002 ; Wistuba et al., 2003). There are three types of spermatogonia described, stem cell spermatogonia, proliferative spermatogonia and differentiating spermatogonia. The stem cells and the proliferating spermatogonial cells are also known as undifferentiated spermatogonia. Type A spermatogonia are undifferentiated spermatogonia, while spermatogonia of type B have already started to differentiate (Russel et al., 1990). A striking difference between non-primates and primates lies in the process of spermatogonial development. Primates, including man, have two types of A spermatogonia : A-pale and A-dark (Clermont, 1969; Meistrich & van Beek, 1993 for details). The A-dark spermatogonia are thought to be reserve stem cells that do not divide under normal conditions of spermatogenesis but start proliferating in response to severe testicular damage, e.g. after irradiation or exposure to antiproliferative drugs (van Alphen, van de Kant & de Rooij, 1988). The A-pale spermatogonia divide during every spermatogenic cycle and provide daughter cells that enter spermatogenesis and replenish the available pool of developing germ cells (Ehmcke, Luetjens & Schlatt, 2004). Hence, these cells are termed renewing stem cells. This is in sharp contrast to the situation in rodents, in which several generations of A-type stem spermatogonia and also several generations of proliferating A-type spermatogonia coexist (Russel et al., 1990 ; de Rooij & Grootegoed, 1998 for details). Recent work suggests that in the immature rat testis, the spermatogonial system is morphologically similar to that of primates (Dettin et al., 2003). Whether this morphological similarity of stem spermatogonia between the immature rodent testis and the adult primate testis is also reflected in a similar physiology and regulation is currently unknown. These preliminary data, however, might suggest that the reserve stem cell/renewing stem cell concept also applies to an early phase of rodent testicular development.

II. BASIC AND SPECIFIC FEATURES OF SPERMATOGENESIS

III. ORGANISATION OF THE SEMINIFEROUS EPITHELIUM

The basic spermatogenic processes yielding male gametes are similar among mammals. Spermatogenesis comprises

The mammalian seminiferous epithelium is characterised by specific germ cell associations derived from particular

I. INTRODUCTION

Primate spermatogenesis topographic relationships of the developing and proliferating germ cells (Sharpe, 1994) denoted as stages of spermatogenesis. A tubular cross section contains either a single germ cell association (single-stage tubule, i.e. one spermatogenic stage per tubular cross section) or different germ cell associations (multi-stage tubule: more than one spermatogenic stage per tubular cross section) (Figs 1 and 2). Although it is possible to define spermatogenic stages for different primate species (e.g. Clermont & Antar, 1973; Chowdury & Steinberger, 1976 ; de Rooij, van Alphen & van de Kant, 1986 ; Haider et al., 1989; Zhengwei et al., 1997 ; Aslam et al., 2002), the six-stage scheme established for human spermatogenesis (Clermont, 1963) can be adapted to describe germ cell associations in the common marmoset (Weinbauer et al., 2001a), the cynomolgus monkey (Dietrich et al., 1986) and many other nonhuman primate species (Wistuba et al., 2003) (Table 1, Fig. 1). Wistuba et al. (2003) used this approach in a systematic analysis of the organisation of the seminiferous epithelium in different species. Since some primates exhibit distinct seasonality of reproductive functions (Zuckerman, 1953; Sade, 1964 ; Conaway & Sade, 1965; Pasqualini et al., 1986 ; Gupta et al., 2000 ; Muehlenbein et al., 2002; Bansode, Chowdhury & Dhar, 2003 ; de B. Vaz Guimaraes, Alvarenga de Oliveira & Campanarut Barnabe, 2003), it is essential that such studies are conducted on testes collected from animals that are fertile and sexually active. The reasons behind the evolution of single-stage and multi-stage tubules are not clear. For the human testis it has been suggested that a patchy arrangement due to a helical organisation of the seminiferous epithelium rather than a segmental sequence (Fig. 2A) of spermatogenic stages causes multi-stage organisation (Schulze & Rehder, 1984 ; Zannini et al., 1999). Supporting evidence for this has not been found in other studies (Johnson, 1994 ; Johnson, McKenzie & Snell, 1996). Alternatively, variation in clonal size could lead to multi-stage organisation (Fig. 2B) (Zhengwei et al., 1997 ; for further discussion see Wistuba et al., 2003). All germ cells within a given spermatogenic clone are derived from one stem cell (Ren & Russell, 1991 ; Alastalo et al., 1998), as has been demonstrated during germ cell transplantation studies (Brinster & Avarbock, 1994; Brinster & Zimmermann, 1994; Nagano, McCarrey & Brinster, 2001). It is, therefore, conceivable that small irregularly organised clones are associated with the multi-stage arrangement whereas large regularly arranged clones constitute the single-stage organisation (see Fig. 2). The occurrence of single- and multi-stage tubules is species-specific. Whilst rodent and tree shrew (Tupaia sp.) testes contain single-stage tubules, those of the man and the great apes have predominantly multi-stage tubules (Heller & Clermont, 1964; Clermont, 1972 ; Smithwick et al., 1996 ; Wistuba et al., 2003). In New World monkeys (Cebidae and Callitrichidae), multi-stage tubules are also present although this group diverged from the human lineage around 35 million years ago (Maston & Ruvolo, 2002). In Old World monkeys either an intermediate type of organisation has been reported as for the olive baboon (Papio hamadryas anubis Linnaeus, 1758 ; Chowdhury & Marshall, 1980) and the mandrill (Mandrillus sphinx Linnaeus, 1758;

477 Wistuba et al., 2003) or predominantly single-stage tubules prevail as in macaques (Clermont & Leblond, 1959; Clermont & Antar, 1973; Dietrich et al., 1986) and vervet monkeys (Chlorocebus aethiops, formerly Cercopithecus, Linnaeus, 1758 ; Wistuba et al., 2003). Little is known about the organisation of the germinal epithelium in the non-anthropoid species (Lemuridae, Lorisidae and Tarsia), but data obtained so far indicate a single-stage arrangement in the testes of prosimians (Strepsirhini) (Fig. 1C). In a comparative study, the relative proportions of singlestage/multi-stage tubules were determined for all primate evolutionary lineages with the exception of the Haplorhini (Wistuba et al., 2003) (Fig. 3). Strepsirhini exhibited the lowest proportion of multi-stage tubules (