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Andrology Laboratory, ANZAC Research Institute, Concord Hospital (C.M.A., A.G., J.S., M.J., D.J.H.), University of Sydney, Sydney NSW 2139, Australia; Biomedicum Helsinki (F.-P.Z.), University of Helsinki, 00140 Helsinki, Finland; and Institute of Reproductive and Developmental Biology (I.H.), Imperial College London, London W12 ONN, United Kingdom
Address all correspondence and requests for reprints to: Charles M. Allan, ANZAC Research Institute, Concord Hospital, Sydney NSW 2139, Australia. E-mail: charles{at}anzac.edu.au.
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Abstract |
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Introduction |
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-subunit, and both can be simultaneously secreted from the same pituitary gonadotroph cells in response to GnRH (17). Pituitary FSH secretion is regulated by both FSH-mediated inhibin B (18) and LH-mediated steroidal feedback pathways (19), and the testicular actions of FSH and LH ultimately converge on Sertoli cells that express receptors for FSH (20) and the androgens synthesized by Leydig cells in response to LH (21). To circumvent the complexity of these interconnected and experimentally confounding FSH and LH pathways, previous studies have examined FSH replacement after complete loss of all pituitary function after hypophysectomy (22), or after more selective but not always complete gonadotropin loss in GnRH-immunized (23) or GnRH antagonist-treated rats (24). This research focused on the role of FSH in the maintenance or reinitiation of germ cell development, during or after regression of established spermatogenesis, and after the crucial perinatal period of Sertoli cell proliferation. Few studies have addressed the role of FSH in initiating spermatogenic development, and previous animal models lacked the ability to examine the full spermatogenic potential of prenatal and longer-term FSH actions. For example, studies with recombinant human FSH are confounded by its immunogenicity (23, 25), and it is not possible to evaluate prenatal FSH effects by immunoneutralization (26), GnRH antagonists (24, 27), or hypophysectomy (22). To avoid these limitations, contemporary research has used genetically altered mouse models to selectively isolate FSH or LH activity, which can be used to study developmental and longer-term effects of FSH. We recently used a gain-of-function strategy to study the gonadal effects of transgenic (tg) FSH (28, 29) in hypogonadal (hpg) mice functionally deficient in GnRH, LH/androgen, and FSH (30). More recently we used the gonadotropin-deficient hpg background to investigate FSH-independent actions of a mutated activated human FSH receptor (FSHR+) (31). These tg-hpg models provide an opportunity to characterize in vivo FSH activity in the absence of circulating LH. An alternative strategy to isolate FSH effects employed a loss-of-function approach to permanently remove LH function by targeted disruption of the LH receptor (LHR) gene in the presence of endogenous mouse FSH (mFSH) activity (32, 33). Although both strategies have generated models with isolated FSH activity, it remains to be determined whether there are systemic differences in spermatogenic developmental due the lack of LH ligand vs. the absence of LH receptors, or tg vs. endogenous FSH activity. Another distinction between the tg-hpg and LHR-null models is the permanently high pituitary-regulated LH and FSH levels found in LHR-null males (32, 33), compared with the autonomous pituitary-independent tg-FSH or tg-FSHR activity in tg-hpg mice. We now provide a detailed stereological comparison of postnatal development in the seminiferous tubules stimulated by either tg-FSH (28, 29) or tg-FSHR+ (31) in LH/FSH-deficient hpg mice, or by endogenous mFSH in LHR-null animals (33). Our present analysis of these distinct models has provided definitive evidence for the crucial role of FSH in the mitotic proliferation of Sertoli cells and has determined the full capacity of FSH alone to enhance but not complete spermatogenic developmental independently of LH activity.
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Materials and Methods |
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ß.6 and 113 lines expressing human FSH and tg RR.3 and RR.4 lines expressing the activated mutant human FSHR+ were previously described (28, 31). Males expressing tg-FSH or tg-FSHR+ on a gonadotropin-deficient hpg background were obtained by cross-breeding animals heterozygous for the GnRH gene deletion, determined by detection of wild-type (wt), hpg, or tg PCR products as described (2, 28, 31). The ß.6 and 113 lines expressed serum tg-FSH levels in a range found to induce a dose-dependent gonadal response in vivo (28). Animals were housed under controlled conditions (12 h light, 12-h dark cycle, 19–22 C) with ad libitum access to food and water. All animal procedures were approved by the Animal Welfare Committee and performed in accordance with the National Health and Medical Research Council code of practice for the care and use of animals and the NSW Animal Research Act (1985). The preparation and screening of LHR-null animals was previously described (33). Age- and strain-matched control hpg (GnRH-/-) and wt (GnRH+/+ and LHR+/+) males were used for comparison with both tg-hpg (C3Hx101 strain) and LHR-null (129/SvEvxC57BL/6 strain) males.
Tissue collection
Animals at 9–10 wk of age were anesthetized and testes were perfused, collected in Bouin’s fixative, weighed, and embedded in hydroxymethylmethacrylate resin (Technovit 7100, Kulzer and Co., Friedrichsdorf, Germany) as described (29). Tissue sections were cut using a Polycut S microtome (Reichert Jung, Nossloch, Germany). Thin sections (3–5 µm) were stained with 0.5% toluidine blue; thick sections (20–25 µm) for stereology were consecutively stained with periodic-acid-schiff, hematoxylin, and Scott’s blue solution.
Quantitation of serum FSH and intratesticular testosterone levels
Serum levels of mouse or tg human FSH were determined in duplicate by immunofluorometric assays (DELFIA, PerkinElmer-Wallac, Turku, Finland) as previously described (28, 33, 34). Intratesticular testosterone levels were measured in duplicate by RIA as previously described (35), except samples were extracted in 10 vol of hexane:ethyl acetate (3:2 vol/vol, pestiscan grade, Labscan, Dublin, Ireland).
Stereological analysis
Testicular Sertoli and germ cell populations were quantified using the optical-disector technique as described (29). Briefly, random uniform sampling of fixed tissue sections (20–25 µm thick, three per testis) was performed by light microscopy (x100/1.35 oil-immersion objective) using unbiased sample frames created by Olympus CAST grid software (Olympus Corp., Albertslund, Denmark). Total Sertoli and germ cell numbers were extrapolated from calculated cell densities of the random sample volumes using respective testis weights and specific gravity of testis (d = 1.04 g/ml) (36). Gonadotropin-independent germ cell development in hpg testes does not follow the defined stages of normal spermatogenesis; therefore, germ cell estimates were broadly grouped into cell types [spermatogonia, preleptone-zygotene spermatocytes, pachytene spermatocytes (PS), round and elongated spermatids] that enabled more complete comparisons between tg-hpg testes and other experimental groups.
Data analysis
All statistical analysis was performed using SPSS version 11.0 (SPSS Inc., Chicago, IL). Normally distributed data (Shapiro-Wilk test) were analyzed using one-way ANOVA with Tamhane post hoc tests. Differences were regarded significant when P < 0.05. All data are presented as mean ± SEM.
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Results |
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ß.6 hemizygous (+/-) tg-FSH hpg animals were increased 4.6-fold relative to non-tg hpg controls, to reach 12% of wt controls (Fig. 1
). Testis sizes of tg-FSHR+ (+/-) hpg mice were increased 3.6-fold relative to hpg testes, and reached 9% of wt weight. By comparison, the testes weights of LHR-null mice were 17% of strain-matched LHR+/+ wt animals (Fig. 1). In males used for stereology, serum mouse FSH levels in LHR-/- males (42.2 ± 5.7 µg/liter, n = 5) were 2-fold higher than wt mice (20.9 ± 1.9 µg/liter, n = 5). Intratesticular testosterone levels in LHR-/- males were not available (testes fixed), but were previously shown to be less than 5% of normal (33). To further test the effects of tg-FSH, homozygous (+/+) ß.6 littermates and line 113 tg-FSH hpg males were also obtained expressing higher levels of circulating FSH (28), which provided a range of testes sizes that were positively correlated with serum FSH levels, reaching up to 29% of wt (non-hpg, non-tg) weight (Fig. 1, middle panel). Intratesticular testosterone concentrations in these tg-hpg males were not correlated with testis size (Fig. 1) or serum tg-FSH levels (r = 0.013).
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, insets). Stereological analysis further revealed that FSH and FSHR+ expression in tg(+/-) hpg males increased absolute Sertoli cell numbers 1.8- and 2.3-fold compared with control hpg testes (Fig. 3). In addition, serum tg-FSH levels dose-dependently increased hpg Sertoli cell numbers to non-hpg wt levels (Fig. 4). Total Sertoli cell numbers in the LHR-null testes were equivalent to wt values (Fig. 3).
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ß.6 line) or FSHR+ in tg(+/-) hpg males significantly increased the absolute numbers of spermatogonial cells 2.5- or 2-fold, respectively (Fig. 3
), compared with non-tg hpg controls. In addition, higher levels of serum tg-FSH (+/+ or 113 males) dose-dependently increased spermatogonia numbers to 57% of wt levels (Fig. 4). Total spermatogonial numbers observed in LHR-null testes were 45% of wt values (Fig. 3).
Spermatocytes.
Compared with undeveloped hpg testes, the numbers of early preleptotene-to-zygotene spermatocytes (Sc) were increased 5- and 3-fold in FSH and FSHR+ tg(+/-) hpg testes, respectively, which were equivalent to 36 or 21% of wt levels. However, higher serum tg-FSH expression increased Sc numbers in hpg testes to 58% of wt, which was similar to the total Sc numbers (57% of normal) observed in LHR-null testes. FSH and FSHR+ significantly increased PS 24- and 19-fold in tg(+/-) hpg testes relative to hpg controls, to levels 16 and 13% of wt (Fig. 3). Serum tg-FSH dose-dependently increased total PS numbers to 37% of wt (Fig. 4), which was higher than the PS numbers (26% of wt) found in LHR-null mice.
Spermatids.
The production of postmeiotic round spermatids (2–3% of wt) was equivalent in both tg(+/-) hpg models and LHR-null mice (Fig. 3). Some seminiferous tubules of tg-FSH and tg-FSHR+ hpg testes contained sparse numbers of elongated spermatids (Fig. 2). In contrast, no elongated spermatids were detected in any of the five LHR-null testes examined (Figs. 2 and 3). Higher levels of circulating tg-FSH produced a marked increase in the numbers of both round and elongated spermatids (Fig. 4), which reached 16 and 6% of wt levels. The intratesticular testosterone levels in these tg-FSH hpg males were not correlated to the observed changes in spermatids or any other germ cell population (data not shown). Sertoli and germ cell development were equivalent for all cell populations examined in the 9-wk-old wt males of the C3H/101 or 129/SvEvxC57BL/6 strains used to generate the tg-hpg or LHR-null models, respectively (Fig. 3).
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Discussion |
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Sertoli cell maturation and proliferation was observed in all three models with FSH activity but lacking the LH response. One advantage of the tg-hpg paradigm compared with the LHR-null approach, which had elevated endogenous FSH and LH levels (32, 33), is that the magnitude of the specific FSH response can be selected independently of GnRH and LH actions, or androgen feedback, using tg lines expressing a range of FSH levels (28). Higher levels of tg-FSH did not increase intratesticular testosterone levels in hpg mice, supporting earlier work that showed FSH alone does not increase androgen levels in hpg testes (37). In the present study, the dose-dependent effects of tg-FSH on final Sertoli cell numbers in hpg testes provided definitive evidence that FSH can stimulate normal Sertoli cell proliferation independently of circulating LH. Likewise, analysis of LHR-null testes showed that Leydig cell LHR-mediated activity is not required for normal Sertoli cell proliferation. A role for LH during normal Sertoli cell proliferation cannot be entirely excluded because these models may exhibit higher than normal FSH activity, noting the elevated FSH levels in LHR-/- males (33), which may compensate for any lost LH function. However, our findings have demonstrated the role of FSH as the primary Sertoli cell mitogen, and further revealed that LH or LHR-mediated activity is not required for the full Sertoli cell complement of the testis.
The current study showed that in the absence of LH activity FSH alone is a major regulator of postnatal germ cell development. Expression of tg-FSH or tg-FSHR+ increased the spermatogonial population in LH-deficient hpg testes. Tg-FSH alone dose-dependently increased total spermatogonia numbers up to 57% of normal testis value, doubling the spermatogonia that occur in the absence of FSH and LH. By comparison, total spermatogonia numbers in LHR-/- testes were 45% of normal, despite the elevated levels of endogenous circulating FSH in LHR-null mice (32, 33). These similar observations suggest FSH activity accounts for approximately half of the final spermatogonial population in a normal mouse testis, which supports early rat studies suggesting FSH stimulates the postnatal mitotic activity of spermatogonia (38). The full proliferation or survival of spermatogonia during testicular development most likely requires the addition of LH-dependent activity presumably via testosterone effects. Studies in hypophysectomized rats showed androgens partially restore spermatogonia maturation (39, 40). Although recent stereological analysis showed testosterone administered at weaning (3 wk old) had little effect on spermatogonia numbers in hpg testes, with or without tg FSH expression (29), it is possible postnatal androgen actions (before weaning age) are necessary for the proposed complementary LH-mediated effects on spermatogonial proliferation. The stimulatory effects of FSH on spermatogonia may be functionally linked with temporal mitogenic effects of FSH on Sertoli cells during perinatal development (41). We propose that FSH promotes the mitotic proliferation of Sertoli cells and (indirectly) spermatogonia when early postnatal Sertoli cells express very limited levels of the androgen receptor (42, 43). Because androgen receptor levels increase during Sertoli cell postnatal development, FSH- and LH-mediated androgen responses mediated via Sertoli cells may further induce and maintain full spermatogonial proliferation. The tg-hpg model provides the opportunity to further investigate the proposed postnatal response to combined FSH-androgen actions, which may not be possible in the LHR-null mouse model due to negative androgenic feedback regulation on pituitary-dependent FSH secretion (44).
Expression of tg-FSH or tg-FSHR+ activity in hpg males promoted the development of early (preleptotene to zygotene) and later stage (pachytene) spermatocytes. In addition, tg-FSH dose-dependently increased total meiotic germ cell numbers in hpg testes to 44% of wt testes. The formation of approximately half of the meiotic population by FSH, independently of LH-mediated events, strongly supports our proposal that spermatocyte development is equally dependent upon FSH- and LH-regulated testosterone production, based on the additive FSH and testosterone effects on hpg meiosis (29). The present analysis also revealed a subtle difference in the final level of meiotic germ cell development in tg-hpg and LHR-null models. Although higher serum tg-FSH levels in hpg males produced early spermatocyte numbers that were equivalent to values in LHR-/- males (58 vs. 57% of wt testis levels), total PS were up to 42% higher in tg-FSH hpg relative to LHR-/- mice (37 vs. 26% of normal). This extrameiotic development in hpg males may reflect differences in background steroidogenesis, as our previous research demonstrated that the meiotic progression of PS is the most androgen-sensitive stage in mouse spermatogenesis (2, 45). The absence of the LHR may have more severe effects on intratesticular testosterone [<5% of wt (32, 33)] compared with the loss of circulating LH [15% of wt (29, 31)]. Regardless of the meiotic difference, our analysis of tg-hpg and LHR-null testes has clearly shown that FSH alone provides a significant albeit subnormal level of meiotic germ cell development independently of LH-mediated actions.
In the present study, FSH activity alone stimulated a limited degree of postmeiotic development in all three models lacking LH activity. Our findings further revealed that tg FSH or FSHR+ hpg testes supported more advanced postmeiotic germ cell development compared with LHR-/- testes. Elongated spermatids were observed in both tg-hpg models, whereas spermatogenesis in LHR-null males was arrested at the round spermatid stage, with no observed elongated spermatid formation. FSH and androgens have strong synergistic effects on postmeiotic development (29); therefore, even lower testicular testosterone may explain the less advanced spermiogenesis in LHR-null testes relative to LH-deficient tg-hpg testes. An underlying mechanism for relatively higher androgen production in tg-hpg compared with LHR-null testes remains unknown. Autonomous FSH activity in tg-hpg mice, independent of the negative feedback pathways of the hypothalamic-pituitary-gonadal axis, may have a greater capacity to enhance reported stimulatory effects of FSH on Leydig cell steroidogenesis (46) compared with pituitary-regulated FSH in the LHR-null mice. Alternatively, the elevated FSH levels in LHR-/- mice may down-regulate Sertoli cell FSHR function (47). Recently, subtle differences in testicular phenotypes between mice lacking either the FSH ligand (3) or FSHR (5) were proposed to reflect the presence of constitutive FSHR activity in the absence of hormone ligand (48), consistent with our earlier proposal that constitutive FSHR signaling can stimulate low levels of steroidogenesis, independently of circulating LH and FSH (31). The absence of FSHRs reduced serum and intratesticular testosterone levels below normal (5, 48), which contrasted with normal circulating and intratesticular testosterone levels found in FSH-ß knockout mice (3). It is undetermined whether the presence or absence of the LHR in Leydig cells confers different basal levels of steroidogenesis in vivo independently of LH ligand; however, in vitro studies have found LHR expression provided no detectable basal activity (via cAMP) in the absence of LH (49, 50, 51).
Our analysis of the three current mouse models has revealed that FSH activity alone, at sufficient levels to fully restore Sertoli cell numbers independently of LH-mediated actions, was not able to support the full completion of spermiogenesis. The analysis of dose-dependent tg-FSH actions on spermatid numbers further suggested that there is a threshold for the induction of postmeiotic spermatid development by FSH; spermatids were only observed with serum tg-FSH levels more than 2 IU/liter and our previous research showed tg-FSH levels less than 1 IU/liter had no effect on testicular development (28). However, it is noteworthy that spermatogenesis observed in tg-hpg and LHR-null models was more advanced than germ cell development previously reported in androgen receptor-deficient males (52, 53). Tubules in androgen receptor-null testes exhibited a more disrupted phenotype with degenerating Sertoli cells and more variable germ cell defects, ranging from Sertoli cell-only regions to others supporting occasional pachytene development. Taken together these findings suggest a complete loss of androgen receptor function is associated with more a severe spermatogenic arrest than selective LH or LHR deficiency, which may provide residual testosterone activity.
In summary, our present analysis of distinct genetic models with selective FSH activity has provided definitive evidence for the crucial role of FSH in determining the mitotic proliferation of Sertoli cells, and its significant role in stimulating mitotic germ cell proliferation and meiotic germ cell development, whereas the limited and incomplete postmeiotic development initiated by FSH demonstrated LH activity is essential for the completion of spermatogenic development.
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Footnotes |
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Abbreviations: FSHR, FSH receptor; hpg, hypogonadal; LHR, LH receptor; mFSH, mouse FSH; PS, pachytene spermatocytes; Sc, early preleptotene-to-zygotene spermatocytes; tg, transgenic; wt, wild-type.
Received September 4, 2003.
Accepted for publication January 7, 2004.
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